bims-mitdis Biomed News
on Mitochondrial disorders
Issue of 2023–06–18
48 papers selected by
Catalina Vasilescu, Helmholz Munich
  1. How does mitochondrial import machinery fine-tune mitophagy? Different paths and one destination.
  2. A mitochondrial iron-responsive pathway regulated by DELE1.
  3. Aggregation prone Tau impairs mitochondrial import, which affects organelle morphology and neuronal complexity.
  4. Role of Mutations of Mitochondrial Aminoacyl-tRNA Synthetases Genes on Epileptogenesis.
  5. The C-Terminal Tail of Mitochondrial Transcription Factor A Is Dispensable for Mitochondrial DNA Replication and Transcription In Situ.
  6. The mitochondrial calcium uniporter (MCU) activates mitochondrial respiration and enhances mobility by regulating mitochondrial redox state.
  7. Oxygen-Independent Assays to Measure Mitochondrial Function in Mammals.
  8. Temporal evolution of the heart failure phenotype in Barth syndrome and treatment with elamipretide.
  9. Mitochondria: at the crossroads between mechanobiology and cell metabolism.
  10. Neurological Phenotypes in Mouse Models of Mitochondrial Disease and Relevance to Human Neuropathology.
  11. Time-resolved proteomic analyses of senescence highlight metabolic rewiring of mitochondria.
  12. The disease-causing mutation p.F907I reveals a novel pathogenic mechanism for POLγ-related diseases.
  13. PERK signaling promotes mitochondrial elongation by remodeling membrane phosphatidic acid.
  14. Reduced acetylation of TFAM promotes bioenergetic dysfunction in the failing heart.
  15. In search for mitochondrial biomarkers of Parkinson's disease: Findings in parkin-mutant human fibroblasts.
  16. Dynamic Patterns of Mammalian Mitochondrial DNA Replication Uncovered Using SSiNGLe-5'ES.
  17. Endogenous TOM20 Proximity Labeling: A Swiss-Knife for the Study of Mitochondrial Proteins in Human Cells.
  18. A worm's life: AMPK links muscle mitochondrial dynamics to physical fitness and healthy aging in Caenorhabditis elegans.
  19. Ex vivo immunocapture and functional characterization of cell-type-specific mitochondria using MitoTag mice.
  20. Nicotinamide riboside functions during development while beta-hydroxybutyrate functions during adulthood to extend C. elegans lifespan.
  21. Horizontal proton transfer across the antiporter-like subunits in mitochondrial respiratory complex I.
  22. Detection of Mitophagy in Caenorhabditis elegans and Mammalian Cells Using Organelle-Specific Dyes.
  23. Mitochondrial complex III activity: from invasive muscle biopsies to patient-friendly buccal swab analysis.
  24. Unravelling the genetic architecture of human complex traits through whole genome sequencing.
  25. Acute Encephalopathy Caused by Inherited Metabolic Diseases.
  26. Homo cerevisiae-Leveraging Yeast for Investigating Protein-Protein Interactions and Their Role in Human Disease.
  27. Systematic Approaches to Study Eclipsed Targeting of Proteins Uncover a New Family of Mitochondrial Proteins.
  28. Mitochondrial quality control in cardiac fibrosis: Epigenetic mechanisms and therapeutic strategies.
  29. Restoration of CPEB4 prevents muscle stem cell senescence during aging.
  30. Role of A-Kinase Anchoring Protein 1 in Retinal Ganglion Cells: Neurodegeneration and Neuroprotection.
  31. Branched-chain keto acids inhibit mitochondrial pyruvate carrier and suppress gluconeogenesis in hepatocytes.
  32. Characterizing the Neuron-Glial Interactions by the Co-cultures of Human iPSC-Derived Oligodendroglia and Neurons.
  33. Statistical methods and resources for biomarker discovery using metabolomics.
  34. Implementation of Nanopore sequencing as a pragmatic workflow for copy number variant confirmation in the clinic.
  35. The crosstalk between ferroptosis and mitochondrial dynamic regulatory networks.
  36. Beyond vacuolar pathology: Multiomic profiling of Danon disease reveals dysfunctional mitochondrial homeostasis.
  37. Mitochondrial Transfer to Host Cells from Ex Vivo Expanded Donor Hematopoietic Stem Cells.
  38. Mitochondrial DNA methylation in metabolic associated fatty liver disease.
  39. MIRO-1 interacts with VDAC-1 to regulate mitochondrial membrane potential in Caenorhabditis elegans.
  40. The mRNA translation initiation factor eIF4G1 controls mitochondrial oxidative phosphorylation, axonal morphogenesis, and memory.
  41. The application of nucleic acid nanomaterials in the treatment of mitochondrial dysfunction.
  42. Hexokinase dissociation from mitochondria promotes oligomerization of VDAC that facilitates NLRP3 inflammasome assembly and activation.
  43. Spinocerebellar ataxia type 11 (SCA11): An update.
  44. NAD DEFICIENCY AND ITS IMPACT ON MAMMALIAN DEVELOPMENT.
  45. iPSC-Based Modeling of Variable Clinical Presentation in Hypertrophic Cardiomyopathy.
  46. Brightness and shadows of mitochondrial ROS in the brain.
  47. Mitochondria-targeted nanoparticles in treatment of neurodegenerative diseases.
  48. Machine learning in computational histopathology: Challenges and opportunities.
  1. Trends Endocrinol Metab. 2023 Jun 13. pii: S1043-2760(23)00107-8. [Epub ahead of print]
    How does mitochondrial import machinery fine-tune mitophagy? Different paths and one destination.
    Mohamed A Eldeeb, Andrea Soumbasis, Edward A Fon.
      Given their polyvalent roles, an intrinsic challenge that mitochondria face is the continuous exposure to various stressors including mitochondrial import defects, which leads to their dysfunction. Recent work has unveiled a presequence translocase-associated import motor (PAM) complex-dependent quality control pathway whereby misfolded proteins mitigate mitochondrial protein import and subsequently elicit mitophagy without the loss of mitochondrial membrane potential.
    Keywords:  PINK1; TOM complex; mitochondrial import; mitochondrial quality control; mitophagy; protein quality control
    DOI:  https://doi.org/10.1016/j.tem.2023.05.005
  2. Mol Cell. 2023 Jun 15. pii: S1097-2765(23)00413-6. [Epub ahead of print]83(12): 2059-2076.e6
    A mitochondrial iron-responsive pathway regulated by DELE1.
    Yusuke Sekine, Ryan Houston, Eva-Maria Eckl, Evelyn Fessler, Derek P Narendra, Lucas T Jae, Shiori Sekine.
      The heme-regulated kinase HRI is activated under heme/iron deficient conditions; however, the underlying molecular mechanism is incompletely understood. Here, we show that iron-deficiency-induced HRI activation requires the mitochondrial protein DELE1. Notably, mitochondrial import of DELE1 and its subsequent protein stability are regulated by iron availability. Under steady-state conditions, DELE1 is degraded by the mitochondrial matrix-resident protease LONP1 soon after mitochondrial import. Upon iron chelation, DELE1 import is arrested, thereby stabilizing DELE1 on the mitochondrial surface to activate the HRI-mediated integrated stress response (ISR). Ablation of this DELE1-HRI-ISR pathway in an erythroid cell model enhances cell death under iron-limited conditions, suggesting a cell-protective role for this pathway in iron-demanding cell lineages. Our findings highlight mitochondrial import regulation of DELE1 as the core component of a previously unrecognized mitochondrial iron responsive pathway that elicits stress signaling following perturbation of iron homeostasis.
    Keywords:  DELE1; HRI; LONP1; erythroid cells; integrated stress response; iron; mitochondria; mitochondrial import; mitochondrial proteostasis
    DOI:  https://doi.org/10.1016/j.molcel.2023.05.031
  3. J Cell Sci. 2023 Jun 12. pii: jcs.260993. [Epub ahead of print]
    Aggregation prone Tau impairs mitochondrial import, which affects organelle morphology and neuronal complexity.
    Hope I Needs, Kevin A Wilkinson, Jeremy M Henley, Ian Collinson.
      Mitochondrial protein import is essential for organellar biogenesis, and thereby for the sufficient supply of cytosolic ATP-particularly important for cells with high energy demands like neurons. This study explores the prospect of import machinery perturbation as a cause of neurodegeneration instigated by the accumulation of aggregating proteins linked to disease. The aggregation-prone Tau variant (TauP301L) reduces the levels of components of the import machinery of the outer (TOM20) and inner membrane (TIM23) while associating with TOM40. Intriguingly, this interaction affects mitochondrial morphology, but not protein import or respiratory function; raising the prospect of an intrinsic rescue mechanism. Indeed, TauP301L induced the formation of tunnelling nanotubes (TNTs), potentially for the recruitment of healthy mitochondria from neighbouring cells and/or the disposal of mitochondria incapacitated by aggregated Tau. Consistent with this, inhibition of TNT formation (and rescue) reveals Tau-induced import impairment. In primary neuronal cultures, TauP301L induced morphological changes characteristic of neurodegeneration. Interestingly, these effects were mirrored in cells where the import sites were blocked artificially. Our results reveal a link between aggregation-prone Tau and defective mitochondrial import machinery relevant to disease.
    Keywords:  Mitochondria; Mitochondrial import; Mitochondrial morphology.; Neurodegeneration; Neuronal complexity; Tau
    DOI:  https://doi.org/10.1242/jcs.260993
  4. Mol Neurobiol. 2023 Jun 14.
    Role of Mutations of Mitochondrial Aminoacyl-tRNA Synthetases Genes on Epileptogenesis.
    Ling-Yue Kong, Yi-Ze Wu, Run-Qi Cheng, Pei-Han Wang, Bi-Wen Peng.
      Mitochondria are the structures in cells that are responsible for producing energy. They contain a specific translation unit for synthesizing mitochondria-encoded respiratory chain components: the mitochondrial DNA (mt DNA). Recently, a growing number of syndromes associated with the dysfunction of mt DNA translation have been reported. However, the functions of these diseases still need to be precise and thus attract much attention. Mitochondrial tRNAs (mt tRNAs) are encoded by mt DNA; they are the primary cause of mitochondrial dysfunction and are associated with a wide range of pathologies. Previous research has shown the role of mt tRNAs in the epileptic mechanism. This review will focus on the function of mt tRNA and the role of mitochondrial aminoacyl-tRNA synthetase (mt aaRS) in order to summarize some common relevant mutant genes of mt aaRS that cause epilepsy and the specific symptoms of the disease they cause.
    Keywords:  Aminoacyl-tRNA synthetase; Epilepsy; Mitochondrial disorders; Mitochondrial tRNA
    DOI:  https://doi.org/10.1007/s12035-023-03429-1
  5. Int J Mol Sci. 2023 May 29. pii: 9430. [Epub ahead of print]24(11):
    The C-Terminal Tail of Mitochondrial Transcription Factor A Is Dispensable for Mitochondrial DNA Replication and Transcription In Situ.
    Natalya Kozhukhar, Mikhail F Alexeyev.
      Mitochondrial transcription factor A (TFAM) is one of the widely studied but still incompletely understood mitochondrial protein, which plays a crucial role in the maintenance and transcription of mitochondrial DNA (mtDNA). The available experimental evidence is often contradictory in assigning the same function to various TFAM domains, partly owing to the limitations of those experimental systems. Recently, we developed the GeneSwap approach, which enables in situ reverse genetic analysis of mtDNA replication and transcription and is devoid of many of the limitations of the previously used techniques. Here, we utilized this approach to analyze the contributions of the TFAM C-terminal (tail) domain to mtDNA transcription and replication. We determined, at a single amino acid (aa) resolution, the TFAM tail requirements for in situ mtDNA replication in murine cells and established that tail-less TFAM supports both mtDNA replication and transcription. Unexpectedly, in cells expressing either C-terminally truncated murine TFAM or DNA-bending human TFAM mutant L6, HSP1 transcription was impaired to a greater extent than LSP transcription. Our findings are incompatible with the prevailing model of mtDNA transcription and thus suggest the need for further refinement.
    Keywords:  GeneSwap approach; TFAM; mtDNA instability; mtDNA replication; mtDNA transcription
    DOI:  https://doi.org/10.3390/ijms24119430
  6. Redox Biol. 2023 Jun 04. pii: S2213-2317(23)00160-X. [Epub ahead of print]64 102759
    The mitochondrial calcium uniporter (MCU) activates mitochondrial respiration and enhances mobility by regulating mitochondrial redox state.
    Anna Weiser, Aurélie Hermant, Flavien Bermont, Federico Sizzano, Sonia Karaz, Pilar Alvarez-Illera, Jaime Santo-Domingo, Vincenzo Sorrentino, Jerome N Feige, Umberto De Marchi.
      Regulation of mitochondrial redox balance is emerging as a key event for cell signaling in both physiological and pathological conditions. However, the link between the mitochondrial redox state and the modulation of these conditions remains poorly defined. Here, we discovered that activation of the evolutionary conserved mitochondrial calcium uniporter (MCU) modulates mitochondrial redox state. By using mitochondria-targeted redox and calcium sensors and genetic MCU-ablated models, we provide evidence of the causality between MCU activation and net reduction of mitochondrial (but not cytosolic) redox state. Redox modulation of redox-sensitive groups via MCU stimulation is required for maintaining respiratory capacity in primary human myotubes and C. elegans, and boosts mobility in worms. The same benefits are obtained bypassing MCU via direct pharmacological reduction of mitochondrial proteins. Collectively, our results demonstrate that MCU regulates mitochondria redox balance and that this process is required to promote the MCU-dependent effects on mitochondrial respiration and mobility.
    Keywords:  C. elegans; Calcium signaling; MCU; Mitochondria; Redox biology; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.redox.2023.102759
  7. J Vis Exp. 2023 May 19.
    Oxygen-Independent Assays to Measure Mitochondrial Function in Mammals.
    Tenzin Tseyang, Jonathan Valeros, Paula Vo, Jessica B Spinelli.
      The flow of electrons in the mitochondrial electron transport chain (ETC) supports multifaceted biosynthetic, bioenergetic, and signaling functions in mammalian cells. As oxygen (O2) is the most ubiquitous terminal electron acceptor for the mammalian ETC, the O2 consumption rate is frequently used as a proxy for mitochondrial function. However, emerging research demonstrates that this parameter is not always indicative of mitochondrial function, as fumarate can be employed as an alternative electron acceptor to sustain mitochondrial functions in hypoxia. This article compiles a series of protocols that allow researchers to measure mitochondrial function independently of the O2 consumption rate. These assays are particularly useful when studying mitochondrial function in hypoxic environments. Specifically, we describe methods to measure mitochondrial ATP production, de novo pyrimidine biosynthesis, NADH oxidation by complex I, and superoxide production. In combination with classical respirometry experiments, these orthogonal and economical assays will provide researchers with a more comprehensive assessment of mitochondrial function in their system of interest.
    DOI:  https://doi.org/10.3791/65184
  8. Future Cardiol. 2023 Jun 16.
    Temporal evolution of the heart failure phenotype in Barth syndrome and treatment with elamipretide.
    Hani N Sabbah, Carolyn Taylor, Hilary J Vernon.
      Barth syndrome (BTHS) is a rare genetic disorder caused by pathogenic variants in TAFAZZIN leading to reduced remodeled cardiolipin (CL), a phospholipid essential to mitochondrial function and structure. Cardiomyopathy presents in most patients with BTHS, typically appearing as dilated cardiomyopathy (DCM) in infancy and evolving to hypertrophic cardiomyopathy (HCM) resembling heart failure (HF) with preserved ejection fraction (HFpEF) in some patients ≥12 years. Elamipretide localizes to the inner mitochondrial membrane where it associates with CL, improving mitochondrial function, structure and bioenergetics, including ATP synthesis. Numerous preclinical and clinical studies in BTHS and other forms of HF have demonstrated that elamipretide improves left ventricular relaxation by ameliorating mitochondrial dysfunction, making it well suited for therapeutic use in adolescent and adult patients with BTHS.
    Keywords:  Barth syndrome; cardiolipin; cardiomyopathy; elamipretide; mitochondria
    DOI:  https://doi.org/10.2217/fca-2023-0008
  9. Biol Cell. 2023 Jun 16.
    Mitochondria: at the crossroads between mechanobiology and cell metabolism.
    Émilie Su, Catherine Villard, Jean-Baptiste Manneville.
      Metabolism and mechanics are two key facets of structural and functional processes in cells, such as growth, proliferation, homeostasis and regeneration. Their reciprocal regulation has been increasingly acknowledged in recent years: external physical and mechanical cues entail metabolic changes, which in return regulate cell mechanosensing and mechanotransduction. Since mitochondria are pivotal regulators of metabolism, we review here the reciprocal links between mitochondrial morphodynamics, mechanics and metabolism. Mitochondria are highly dynamic organelles which sense and integrate mechanical, physical and metabolic cues to adapt their morphology, the organization of their network and their metabolic functions. While some of the links between mitochondrial morphodynamics, mechanics and metabolism are already well established, others are still poorly documented and open new fields of research. First, cell metabolism is known to correlate with mitochondrial morphodynamics. For instance, mitochondrial fission, fusion and cristae remodeling allow the cell to fine-tune its energy production through the contribution of mitochondrial oxidative phosphorylation and cytosolic glycolysis. Second, mechanical cues and alterations in mitochondrial mechanical properties reshape and reorganize the mitochondrial network. Mitochondrial membrane tension emerges as a decisive physical property which regulates mitochondrial morphodynamics. However, the converse link hypothesizing a contribution of morphodynamics to mitochondria mechanics and/or mechanosensitivity has not yet been demonstrated. Third, we highlight that mitochondrial mechanics and metabolism are reciprocally regulated, although little is known about the mechanical adaptation of mitochondria in response to metabolic cues. Deciphering the links between mitochondrial morphodynamics, mechanics and metabolism still presents significant technical and conceptual challenges but is crucial both for a better understanding of mechanobiology and for potential novel therapeutic approaches in diseases such as cancer. This article is protected by copyright. All rights reserved.
    Keywords:  Mitochondrial morphodynamics; cancer; cytoskeleton; glycolysis; mechanotransduction; membrane tension; oxidative phosphorylation
    DOI:  https://doi.org/10.1111/boc.202300010
  10. Int J Mol Sci. 2023 Jun 02. pii: 9698. [Epub ahead of print]24(11):
    Neurological Phenotypes in Mouse Models of Mitochondrial Disease and Relevance to Human Neuropathology.
    Elizaveta A Olkhova, Laura A Smith, Carla Bradshaw, Gráinne S Gorman, Daniel Erskine, Yi Shiau Ng.
      Mitochondrial diseases represent the most common inherited neurometabolic disorders, for which no effective therapy currently exists for most patients. The unmet clinical need requires a more comprehensive understanding of the disease mechanisms and the development of reliable and robust in vivo models that accurately recapitulate human disease. This review aims to summarise and discuss various mouse models harbouring transgenic impairments in genes that regulate mitochondrial function, specifically their neurological phenotype and neuropathological features. Ataxia secondary to cerebellar impairment is one of the most prevalent neurological features of mouse models of mitochondrial dysfunction, consistent with the observation that progressive cerebellar ataxia is a common neurological manifestation in patients with mitochondrial disease. The loss of Purkinje neurons is a shared neuropathological finding in human post-mortem tissues and numerous mouse models. However, none of the existing mouse models recapitulate other devastating neurological phenotypes, such as refractory focal seizures and stroke-like episodes seen in patients. Additionally, we discuss the roles of reactive astrogliosis and microglial reactivity, which may be driving the neuropathology in some of the mouse models of mitochondrial dysfunction, as well as mechanisms through which cellular death may occur, beyond apoptosis, in neurons undergoing mitochondrial bioenergy crisis.
    Keywords:  cerebellar ataxia; inhibitory neurons; neurodegeneration
    DOI:  https://doi.org/10.3390/ijms24119698
  11. Life Sci Alliance. 2023 Sep;pii: e202302127. [Epub ahead of print]6(9):
    Time-resolved proteomic analyses of senescence highlight metabolic rewiring of mitochondria.
    Jun Yong Kim, Ilian Atanassov, Frederik Dethloff, Lara Kroczek, Thomas Langer.
      Mitochondrial dysfunction and cellular senescence are hallmarks of aging. However, the relationship between these two phenomena remains incompletely understood. In this study, we investigated the rewiring of mitochondria upon development of the senescent state in human IMR90 fibroblasts. Determining the bioenergetic activities and abundance of mitochondria, we demonstrate that senescent cells accumulate mitochondria with reduced OXPHOS activity, resulting in an overall increase of mitochondrial activities in senescent cells. Time-resolved proteomic analyses revealed extensive reprogramming of the mitochondrial proteome upon senescence development and allowed the identification of metabolic pathways that are rewired with different kinetics upon establishment of the senescent state. Among the early responding pathways, the degradation of branched-chain amino acid was increased, whereas the one carbon folate metabolism was decreased. Late-responding pathways include lipid metabolism and mitochondrial translation. These signatures were confirmed by metabolic flux analyses, highlighting metabolic rewiring as a central feature of mitochondria in cellular senescence. Together, our data provide a comprehensive view on the changes in mitochondrial proteome in senescent cells and reveal how the mitochondrial metabolism is rewired in senescent cells.
    DOI:  https://doi.org/10.26508/lsa.202302127
  12. Biochim Biophys Acta Mol Basis Dis. 2023 Jun 09. pii: S0925-4439(23)00152-7. [Epub ahead of print] 166786
    The disease-causing mutation p.F907I reveals a novel pathogenic mechanism for POLγ-related diseases.
    Direnis Erdinc, Bertil Macao, Sebastian Valenzuela, Nicole Lesko, Karin Naess, Bradley Peter, Helene Bruhn, Anna Wedell, Anna Wredenberg, Maria Falkenberg.
      Mutations in the catalytic domain of mitochondrial DNA polymerase γ (POLγ) cause a broad spectrum of clinical conditions. POLγ mutations impair mitochondrial DNA replication, thereby causing deletions and/or depletion of mitochondrial DNA, which in turn impair biogenesis of the oxidative phosphorylation system. We here identify a patient with a homozygous p.F907I mutation in POLγ, manifesting a severe clinical phenotype with developmental arrest and rapid loss of skills from 18 months of age. Magnetic resonance imaging of the brain revealed extensive white matter abnormalities, Southern blot of muscle mtDNA demonstrated depletion of mtDNA and the patient deceased at 23 months of age. Interestingly, the p.F907I mutation does not affect POLγ activity on single-stranded DNA or its proofreading activity. Instead, the mutation affects unwinding of parental double-stranded DNA at the replication fork, impairing the ability of the POLγ to support leading-strand DNA synthesis with the TWINKLE helicase. Our results thus reveal a novel pathogenic mechanism for POLγ-related diseases.
    Keywords:  DNA polymerase γ; Disease; Mitochondrial replication; TWINKLE helicase; mtDNA
    DOI:  https://doi.org/10.1016/j.bbadis.2023.166786
  13. EMBO J. 2023 Jun 12. e113908
    PERK signaling promotes mitochondrial elongation by remodeling membrane phosphatidic acid.
    Valerie Perea, Christian Cole, Justine Lebeau, Vivian Dolina, Kelsey R Baron, Aparajita Madhavan, Jeffery W Kelly, Danielle A Grotjahn, R Luke Wiseman.
      Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are linked in the onset and pathogenesis of numerous diseases. This has led to considerable interest in defining the mechanisms responsible for regulating mitochondria during ER stress. The PERK signaling arm of the unfolded protein response (UPR) has emerged as a prominent ER stress-responsive signaling pathway that regulates diverse aspects of mitochondrial biology. Here, we show that PERK activity promotes adaptive remodeling of mitochondrial membrane phosphatidic acid (PA) to induce protective mitochondrial elongation during acute ER stress. We find that PERK activity is required for ER stress-dependent increases in both cellular PA and YME1L-dependent degradation of the intramitochondrial PA transporter PRELID1. These two processes lead to the accumulation of PA on the outer mitochondrial membrane where it can induce mitochondrial elongation by inhibiting mitochondrial fission. Our results establish a new role for PERK in the adaptive remodeling of mitochondrial phospholipids and demonstrate that PERK-dependent PA regulation adapts organellar shape in response to ER stress.
    Keywords:  endoplasmic reticulum (ER) stress; mitochondrial morphology; phosphatidic acid; unfolded protein response (UPR)
    DOI:  https://doi.org/10.15252/embj.2023113908
  14. iScience. 2023 Jun 16. 26(6): 106942
    Reduced acetylation of TFAM promotes bioenergetic dysfunction in the failing heart.
    Manling Zhang, Ning Feng, Zishan Peng, Dharendra Thapa, Michael W Stoner, Janet R Manning, Charles F McTiernan, Xue Yang, Michael J Jurczak, Danielle Guimaraes, Krithika Rao, Sruti Shiva, Brett A Kaufman, Michael N Sack, Iain Scott.
      General control of amino acid synthesis 5-like 1 (GCN5L1) was previously identified as a key regulator of protein lysine acetylation in mitochondria. Subsequent studies demonstrated that GCN5L1 regulates the acetylation status and activity of mitochondrial fuel substrate metabolism enzymes. However, the role of GCN5L1 in response to chronic hemodynamic stress is largely unknown. Here, we show that cardiomyocyte-specific GCN5L1 knockout mice (cGCN5L1 KO) display exacerbated heart failure progression following transaortic constriction (TAC). Mitochondrial DNA and protein levels were decreased in cGCN5L1 KO hearts after TAC, and isolated neonatal cardiomyocytes with reduced GCN5L1 expression had lower bioenergetic output in response to hypertrophic stress. Loss of GCN5L1 expression led to a decrease in the acetylation status of mitochondrial transcription factor A (TFAM) after TAC in vivo, which was linked to a reduction in mtDNA levels in vitro. Together, these data suggest that GCN5L1 may protect from hemodynamic stress by maintaining mitochondrial bioenergetic output.
    Keywords:  Hematology; Molecular biology; Physiology
    DOI:  https://doi.org/10.1016/j.isci.2023.106942
  15. Biochim Biophys Acta Mol Basis Dis. 2023 Jun 10. pii: S0925-4439(23)00153-9. [Epub ahead of print]1869(7): 166787
    In search for mitochondrial biomarkers of Parkinson's disease: Findings in parkin-mutant human fibroblasts.
    Iryna Kamienieva, Agata Charzyńska, Jerzy Duszyński, Dominika Malińska, Joanna Szczepanowska.
      Most cases of Parkinson's disease (PD) are idiopathic, with unknown aetiology and genetic background. However, approximately 10 % of cases are caused by defined genetic mutations, among which mutations in the parkin gene are the most common. There is increasing evidence of the involvement of mitochondrial dysfunction in the development of both idiopathic and genetic PD. However, the data on mitochondrial changes reported by different studies are inconsistent, which can reflect the variability in genetic background of the disease. Mitochondria, as a plastic and dynamic organelles, are the first place in the cell to respond to external and internal stress. In this work, we characterized mitochondrial function and dynamics (network morphology and turnover regulation) in primary fibroblasts from PD patients with parkin mutations. We performed clustering analysis of the obtained data to compare the profiles of mitochondrial parameters in PD patients and healthy donors. This allowed to extract the features characteristic for PD patients fibroblasts, which were a smaller and less complex mitochondrial network and decreased levels of mitochondrial biogenesis regulators and mitophagy mediators. The approach we used allowed a comprehensive characteristics of elements common for mitochondrial dynamics remodelling accompanying pathogenic mutation. This may be helpful in the deciphering key pathomechanisms of the PD disease.
    Keywords:  Mitochondria; Parkin; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.bbadis.2023.166787
  16. Int J Mol Sci. 2023 Jun 03. pii: 9711. [Epub ahead of print]24(11):
    Dynamic Patterns of Mammalian Mitochondrial DNA Replication Uncovered Using SSiNGLe-5'ES.
    Dongyang Xu, Lingcong Luo, Yu Huang, Meng Lu, Lu Tang, Yong Diao, Philipp Kapranov.
      The proper replication of mitochondrial DNA is key to the maintenance of this crucial organelle. Multiple studies aimed at understanding the mechanisms of replication of the mitochondrial genome have been conducted in the past several decades; however, while highly informative, they were conducted using relatively low-sensitivity techniques. Here, we established a high-throughput approach based on next-generation sequencing to identify replication start sites with nucleotide-level resolution and applied it to the genome of mitochondria from different human and mouse cell types. We found complex and highly reproducible patterns of mitochondrial initiation sites, both previously annotated and newly discovered in this work, that showed differences among different cell types and species. These results suggest that the patterns of the replication initiation sites are dynamic and might reflect, in some yet unknown ways, the complexities of mitochondrial and cellular physiology. Overall, this work suggests that much remains unknown about the details of mitochondrial DNA replication in different biological states, and the method established here opens up a new avenue in the study of the replication of mitochondrial and potentially other genomes.
    Keywords:  SSiNGLe-5′ES; mitochondria; mitochondrial genome; origin of DNA replication
    DOI:  https://doi.org/10.3390/ijms24119711
  17. Int J Mol Sci. 2023 May 31. pii: 9604. [Epub ahead of print]24(11):
    Endogenous TOM20 Proximity Labeling: A Swiss-Knife for the Study of Mitochondrial Proteins in Human Cells.
    Sébastien Meurant, Lorris Mauclet, Marc Dieu, Thierry Arnould, Sven Eyckerman, Patricia Renard.
      Biotin-based proximity labeling approaches, such as BioID, have demonstrated their use for the study of mitochondria proteomes in living cells. The use of genetically engineered BioID cell lines enables the detailed characterization of poorly characterized processes such as mitochondrial co-translational import. In this process, translation is coupled to the translocation of the mitochondrial proteins, alleviating the energy cost typically associated with the post-translational import relying on chaperone systems. However, the mechanisms are still unclear with only few actors identified but none that have been described in mammals yet. We thus profiled the TOM20 proxisome using BioID, assuming that some of the identified proteins could be molecular actors of the co-translational import in human cells. The obtained results showed a high enrichment of RNA binding proteins close to the TOM complex. However, for the few selected candidates, we could not demonstrate a role in the mitochondrial co-translational import process. Nonetheless, we were able to demonstrate additional uses of our BioID cell line. Indeed, the experimental approach used in this study is thus proposed for the identification of mitochondrial co-translational import effectors and for the monitoring of protein entry inside mitochondria with a potential application in the prediction of mitochondrial protein half-life.
    Keywords:  BioID; co-translational import; mass spectrometry; mitochondria; protein identification
    DOI:  https://doi.org/10.3390/ijms24119604
  18. J Cardiovasc Aging. 2023 ;pii: 25. [Epub ahead of print]3(3):
    A worm's life: AMPK links muscle mitochondrial dynamics to physical fitness and healthy aging in Caenorhabditis elegans.
    Vihang A Narkar.
      
    Keywords:  AMPK; Exercise; mitochondrial dynamics
    DOI:  https://doi.org/10.20517/jca.2023.14
  19. Nat Protoc. 2023 Jun 16.
    Ex vivo immunocapture and functional characterization of cell-type-specific mitochondria using MitoTag mice.
    Natalia Prudente de Mello, Caroline Fecher, Adrian Marti Pastor, Fabiana Perocchi, Thomas Misgeld.
      Mitochondria are key bioenergetic organelles involved in many biosynthetic and signaling pathways. However, their differential contribution to specific functions of cells within complex tissues is difficult to dissect with current methods. The present protocol addresses this need by enabling the ex vivo immunocapture of cell-type-specific mitochondria directly from their tissue context through a MitoTag reporter mouse. While other available methods were developed for bulk mitochondria isolation or more abundant cell-type-specific mitochondria, this protocol was optimized for the selective isolation of functional mitochondria from medium-to-low-abundant cell types in a heterogeneous tissue, such as the central nervous system. The protocol has three major parts: First, mitochondria of a cell type of interest are tagged via an outer mitochondrial membrane eGFP by crossing MitoTag mice to a cell-type-specific Cre-driver line or by delivery of viral vectors for Cre expression. Second, homogenates are prepared from relevant tissues by nitrogen cavitation, from which tagged organelles are immunocaptured using magnetic microbeads. Third, immunocaptured mitochondria are used for downstream assays, e.g., to probe respiratory capacity or calcium handling, revealing cell-type-specific mitochondrial diversity in molecular composition and function. The MitoTag approach enables the identification of marker proteins to label cell-type-specific organelle populations in situ, elucidates cell-type-enriched mitochondrial metabolic and signaling pathways, and reveals functional mitochondrial diversity between adjacent cell types in complex tissues, such as the brain. Apart from establishing the mouse colony (6-8 weeks without import), the immunocapture protocol takes 2 h and functional assays require 1-2 h.
    DOI:  https://doi.org/10.1038/s41596-023-00831-w
  20. MicroPubl Biol. 2023 ;2023
    Nicotinamide riboside functions during development while beta-hydroxybutyrate functions during adulthood to extend C. elegans lifespan.
    J Dylan Peters, McKenzie P Peters, Patrick C Bradshaw.
      Nicotinamide riboside (NR), a form of vitamin B3 and a nicotinamide adenine dinucleotide (NAD + ) precursor, has been shown to activate the mitochondrial unfolded protein response (UPR mt ) and extend the lifespan when supplemented to C. elegans. The ketone body and histone deacetylase (HDAC) inhibitor beta-hydroxybutyrate (BHB) has also been shown to extend C. elegans lifespan. Experiments were performed that showed that NR extended lifespan by acting almost exclusively during larval development, while BHB extended lifespan by acting during adulthood, and the combination of NR during development and BHB during adulthood unexpectedly decreased lifespan. This suggests that hormesis is involved in the lifespan-altering effects of BHB and NR and that they are inducing parallel longevity pathways that converge on a common downstream target.
    DOI:  https://doi.org/10.17912/micropub.biology.000841
  21. Chem Sci. 2023 Jun 14. 14(23): 6309-6318
    Horizontal proton transfer across the antiporter-like subunits in mitochondrial respiratory complex I.
    Oleksii Zdorevskyi, Amina Djurabekova, Jonathan Lasham, Vivek Sharma.
      Respiratory complex I is a redox-driven proton pump contributing to about 40% of total proton motive force required for mitochondrial ATP generation. Recent high-resolution cryo-EM structural data revealed the positions of several water molecules in the membrane domain of the large enzyme complex. However, it remains unclear how protons flow in the membrane-bound antiporter-like subunits of complex I. Here, we performed multiscale computer simulations on high-resolution structural data to model explicit proton transfer processes in the ND2 subunit of complex I. Our results show protons can travel the entire width of antiporter-like subunits, including at the subunit-subunit interface, parallel to the membrane. We identify a previously unrecognized role of conserved tyrosine residues in catalyzing horizontal proton transfer, and that long-range electrostatic effects assist in reducing energetic barriers of proton transfer dynamics. Results from our simulations warrant a revision in several prevailing proton pumping models of respiratory complex I.
    DOI:  https://doi.org/10.1039/d3sc01427d
  22. J Vis Exp. 2023 May 19.
    Detection of Mitophagy in Caenorhabditis elegans and Mammalian Cells Using Organelle-Specific Dyes.
    Vijigisha Srivastava, Einav Gross.
      Mitochondria are essential for various biological functions, including energy production, lipid metabolism, calcium homeostasis, heme biosynthesis, regulated cell death, and the generation of reactive oxygen species (ROS). ROS are vital for key biological processes. However, when uncontrolled, they can lead to oxidative injury, including mitochondrial damage. Damaged mitochondria release more ROS, thereby intensifying cellular injury and the disease state. A homeostatic process named mitochondrial autophagy (mitophagy) selectively removes damaged mitochondria, which are then replaced by new ones. There are multiple mitophagy pathways, with the common endpoint being the breakdown of the damaged mitochondria in lysosomes. Several methodologies, including genetic sensors, antibody immunofluorescence, and electron microscopy, use this endpoint to quantify mitophagy. Each method for examining mitophagy has its advantages, such as specific tissue/cell targeting (with genetic sensors) and great detail (with electron microscopy). However, these methods often require expensive resources, trained personnel, and a lengthy preparation time before the actual experiment, such as for creating transgenic animals. Here, we present a cost-effective alternative for measuring mitophagy using commercially available fluorescent dyes targeting mitochondria and lysosomes. This method effectively measures mitophagy in the nematode Caenorhabditis elegans and human liver cells, which indicates its potential efficiency in other model systems.
    DOI:  https://doi.org/10.3791/65337
  23. Sci Rep. 2023 Jun 14. 13(1): 9638
    Mitochondrial complex III activity: from invasive muscle biopsies to patient-friendly buccal swab analysis.
    Tim Somers, Neeltje A E Allard, Sailay Siddiqi, Margit C M Janssen, Maria T E Hopman, Wim J Morshuis, Frans G M Russel, Silvie Timmers, Tom J J Schirris.
      Drug-induced mitochondrial dysfunction is a common adverse effect, particularly in case of statins-the most prescribed drugs worldwide. These drugs have been shown to inhibit complex III (CIII) of the mitochondrial oxidative phosphorylation process, which is related to muscle pain. As muscle pain is the most common complaint of statin users, it is crucial to distinguish it from other causes of myalgia to prevent unnecessary cessation of drug therapy. However, diagnosing CIII inhibition currently requires muscle biopsies, which are invasive and not practical for routine testing. Less invasive alternatives for measurement of mitochondrial complex activities are only available yet for complex I and IV. Here, we describe a non-invasive spectrophotometric method to determine CIII catalytic activities using buccal swabs, which we validated in a cohort of statin and non-statin users. Our data indicate that CIII can be reliably measured in buccal swabs, as evidenced by reproducible results above the detection limit. Further validation on a large-scale clinical setting is recommended.
    DOI:  https://doi.org/10.1038/s41598-023-36741-w
  24. Nat Commun. 2023 Jun 14. 14(1): 3520
    Unravelling the genetic architecture of human complex traits through whole genome sequencing.
    Ozvan Bocher, Cristen J Willer, Eleftheria Zeggini.
      
    DOI:  https://doi.org/10.1038/s41467-023-39259-x
  25. J Clin Med. 2023 May 31. pii: 3797. [Epub ahead of print]12(11):
    Acute Encephalopathy Caused by Inherited Metabolic Diseases.
    Yohei Sugiyama, Kei Murayama.
      Acute encephalopathy is a critical medical condition that typically affects previously healthy children and young adults and often results in death or severe neurological sequelae. Inherited metabolic diseases that can cause acute encephalopathy include urea cycle disorders, amino acid metabolism disorders, organic acid metabolism disorders, fatty acid metabolism disorders, mutations in the thiamine-transporter gene, and mitochondrial diseases. Although each inherited metabolic disease is rare, its overall incidence is reported as 1 in 800-2500 patients. This narrative review presents the common inherited metabolic diseases that cause acute encephalopathy. Since diagnosing inherited metabolic diseases requires specific testing, early metabolic/metanolic screening tests are required when an inherited metabolic disease is suspected. We also describe the symptoms and history associated with suspected inherited metabolic diseases, the various tests that should be conducted in case of suspicion, and treatment according to the disease group. Recent advancements made in the understanding of some of the inherited metabolic diseases that cause acute encephalopathy are also highlighted. Acute encephalopathy due to inherited metabolic diseases can have numerous different causes, and recognition of the possibility of an inherited metabolic disease as early as possible, obtaining appropriate specimens, and proceeding with testing and treatment in parallel are crucial in the management of these diseases.
    Keywords:  THTR2 (SLC19A3) gene mutation; acute encephalopathy; amino acid metabolism disorders; enoyl-CoA hydratase short-chain 1; fatty acid metabolism disorders; homocystinuria; inherited metabolic disease; liver transplantation; mitochondrial diseases; urea cycle disorders
    DOI:  https://doi.org/10.3390/jcm12113797
  26. Int J Mol Sci. 2023 May 24. pii: 9179. [Epub ahead of print]24(11):
    Homo cerevisiae-Leveraging Yeast for Investigating Protein-Protein Interactions and Their Role in Human Disease.
    Florent Laval, Georges Coppin, Jean-Claude Twizere, Marc Vidal.
      Understanding how genetic variation affects phenotypes represents a major challenge, particularly in the context of human disease. Although numerous disease-associated genes have been identified, the clinical significance of most human variants remains unknown. Despite unparalleled advances in genomics, functional assays often lack sufficient throughput, hindering efficient variant functionalization. There is a critical need for the development of more potent, high-throughput methods for characterizing human genetic variants. Here, we review how yeast helps tackle this challenge, both as a valuable model organism and as an experimental tool for investigating the molecular basis of phenotypic perturbation upon genetic variation. In systems biology, yeast has played a pivotal role as a highly scalable platform which has allowed us to gain extensive genetic and molecular knowledge, including the construction of comprehensive interactome maps at the proteome scale for various organisms. By leveraging interactome networks, one can view biology from a systems perspective, unravel the molecular mechanisms underlying genetic diseases, and identify therapeutic targets. The use of yeast to assess the molecular impacts of genetic variants, including those associated with viral interactions, cancer, and rare and complex diseases, has the potential to bridge the gap between genotype and phenotype, opening the door for precision medicine approaches and therapeutic development.
    Keywords:  edgetics; human variome; interactome; personalized medicine; protein–protein interaction; yeast
    DOI:  https://doi.org/10.3390/ijms24119179
  27. Cells. 2023 Jun 05. pii: 1550. [Epub ahead of print]12(11):
    Systematic Approaches to Study Eclipsed Targeting of Proteins Uncover a New Family of Mitochondrial Proteins.
    Maayan Mark, Ofir Klein, Yu Zhang, Koyeli Das, Adi Elbaz, Reut Noa Hazan, Michal Lichtenstein, Norbert Lehming, Maya Schuldiner, Ophry Pines.
      Dual localization or dual targeting refers to the phenomenon by which identical, or almost identical, proteins are localized to two (or more) separate compartments of the cell. From previous work in the field, we had estimated that a third of the mitochondrial proteome is dual-targeted to extra-mitochondrial locations and suggested that this abundant dual targeting presents an evolutionary advantage. Here, we set out to study how many additional proteins whose main activity is outside mitochondria are also localized, albeit at low levels, to mitochondria (eclipsed). To do this, we employed two complementary approaches utilizing the α-complementation assay in yeast to uncover the extent of such an eclipsed distribution: one systematic and unbiased and the other based on mitochondrial targeting signal (MTS) predictions. Using these approaches, we suggest 280 new eclipsed distributed protein candidates. Interestingly, these proteins are enriched for distinctive properties compared to their exclusively mitochondrial-targeted counterparts. We focus on one unexpected eclipsed protein family of the Triose-phosphate DeHydrogenases (TDH) and prove that, indeed, their eclipsed distribution in mitochondria is important for mitochondrial activity. Our work provides a paradigm of deliberate eclipsed mitochondrial localization, targeting and function, and should expand our understanding of mitochondrial function in health and disease.
    Keywords:  TDH2; TDH3; dual protein targeting; eclipsed protein targeting; mitochondria; yeast model system
    DOI:  https://doi.org/10.3390/cells12111550
  28. Metabolism. 2023 Jun 09. pii: S0026-0495(23)00230-5. [Epub ahead of print]145 155626
    Mitochondrial quality control in cardiac fibrosis: Epigenetic mechanisms and therapeutic strategies.
    Li-Chan Lin, Bin Tu, Kai Song, Zhi-Yan Liu, He Sun, Yang Zhou, Ji-Ming Sha, Jing-Jing Yang, Ye Zhang, Jian-Yuan Zhao, Hui Tao.
      Cardiac fibrosis (CF) is considered an ultimate common pathway of a wide variety of heart diseases in response to diverse pathological and pathophysiological stimuli. Mitochondria are characterized as isolated organelles with a double-membrane structure, and they primarily contribute to and maintain highly dynamic energy and metabolic networks whose distribution and structure exert potent support for cellular properties and performance. Because the myocardium is a highly oxidative tissue with high energy demands to continuously pump blood, mitochondria are the most abundant organelles within mature cardiomyocytes, accounting for up to one-third of the total cell volume, and play an essential role in maintaining optimal performance of the heart. Mitochondrial quality control (MQC), including mitochondrial fusion, fission, mitophagy, mitochondrial biogenesis, and mitochondrial metabolism and biosynthesis, is crucial machinery that modulates cardiac cells and heart function by maintaining and regulating the morphological structure, function and lifespan of mitochondria. Certain investigations have focused on mitochondrial dynamics, including manipulating and maintaining the dynamic balance of energy demand and nutrient supply, and the resultant findings suggest that changes in mitochondrial morphology and function may contribute to bioenergetic adaptation during cardiac fibrosis and pathological remodeling. In this review, we discuss the function of epigenetic regulation and molecular mechanisms of MQC in the pathogenesis of CF and provide evidence for targeting MQC for CF. Finally, we discuss how these findings can be applied to improve the treatment and prevention of CF.
    Keywords:  Cardiac fibrosis; Epigenetics; Extracellular matrix; Mitochondrial quality control
    DOI:  https://doi.org/10.1016/j.metabol.2023.155626
  29. Dev Cell. 2023 Jun 08. pii: S1534-5807(23)00244-7. [Epub ahead of print]
    Restoration of CPEB4 prevents muscle stem cell senescence during aging.
    Wenshu Zeng, Wenxin Zhang, Erin H Y Tse, Jing Liu, Anqi Dong, Kim S W Lam, Shaoyuan Luan, Wai Hing Kung, Tsz Ching Chan, Tom H Cheung.
      Age-associated impairments in adult stem cell functions correlate with a decline in somatic tissue regeneration capacity. However, the mechanisms underlying the molecular regulation of adult stem cell aging remain elusive. Here, we provide a proteomic analysis of physiologically aged murine muscle stem cells (MuSCs), illustrating a pre-senescent proteomic signature. During aging, the mitochondrial proteome and activity are impaired in MuSCs. In addition, the inhibition of mitochondrial function results in cellular senescence. We identified an RNA-binding protein, CPEB4, downregulated in various aged tissues, which is required for MuSC functions. CPEB4 regulates the mitochondrial proteome and activity through mitochondrial translational control. MuSCs devoid of CPEB4 induced cellular senescence. Importantly, restoring CPEB4 expression rescued impaired mitochondrial metabolism, improved geriatric MuSC functions, and prevented cellular senescence in various human cell lines. Our findings provide the basis for the possibility that CPEB4 regulates mitochondrial metabolism to govern cellular senescence, with an implication of therapeutic intervention for age-related senescence.
    Keywords:  CPEB4; aging; mitochondrial metabolism; muscle stem cells; quiescence; senescence
    DOI:  https://doi.org/10.1016/j.devcel.2023.05.012
  30. Cells. 2023 Jun 03. pii: 1539. [Epub ahead of print]12(11):
    Role of A-Kinase Anchoring Protein 1 in Retinal Ganglion Cells: Neurodegeneration and Neuroprotection.
    Tonking Bastola, Guy A Perkins, Keun-Young Kim, Seunghwan Choi, Jin-Woo Kwon, Ziyao Shen, Stefan Strack, Won-Kyu Ju.
      A-Kinase anchoring protein 1 (AKAP1) is a multifunctional mitochondrial scaffold protein that regulates mitochondrial dynamics, bioenergetics, and calcium homeostasis by anchoring several proteins, including protein kinase A, to the outer mitochondrial membrane. Glaucoma is a complex, multifactorial disease characterized by a slow and progressive degeneration of the optic nerve and retinal ganglion cells (RGCs), ultimately resulting in vision loss. Impairment of the mitochondrial network and function is linked to glaucomatous neurodegeneration. Loss of AKAP1 induces dynamin-related protein 1 dephosphorylation-mediated mitochondrial fragmentation and loss of RGCs. Elevated intraocular pressure triggers a significant reduction in AKAP1 protein expression in the glaucomatous retina. Amplification of AKAP1 expression protects RGCs from oxidative stress. Hence, modulation of AKAP1 could be considered a potential therapeutic target for neuroprotective intervention in glaucoma and other mitochondria-associated optic neuropathies. This review covers the current research on the role of AKAP1 in the maintenance of mitochondrial dynamics, bioenergetics, and mitophagy in RGCs and provides a scientific basis to identify and develop new therapeutic strategies that could protect RGCs and their axons in glaucoma.
    Keywords:  AKAP1; DRP1; glaucoma; mitochondrial dynamics; mitochondrial fission; neurodegeneration; neuroprotection; retinal ganglion cell
    DOI:  https://doi.org/10.3390/cells12111539
  31. Cell Rep. 2023 Jun 12. pii: S2211-1247(23)00652-6. [Epub ahead of print]42(6): 112641
    Branched-chain keto acids inhibit mitochondrial pyruvate carrier and suppress gluconeogenesis in hepatocytes.
    Kiyoto Nishi, Akira Yoshii, Lauren Abell, Bo Zhou, Ricardo Frausto, Julia Ritterhoff, Timothy S McMillen, Ian Sweet, Yibin Wang, Chen Gao, Rong Tian.
      Branched-chain amino acid (BCAA) metabolism is linked to glucose homeostasis, but the underlying signaling mechanisms are unclear. We find that gluconeogenesis is reduced in mice deficient of Ppm1k, a positive regulator of BCAA catabolism, which protects against obesity-induced glucose intolerance. Accumulation of branched-chain keto acids (BCKAs) inhibits glucose production in hepatocytes. BCKAs suppress liver mitochondrial pyruvate carrier (MPC) activity and pyruvate-supported respiration. Pyruvate-supported gluconeogenesis is selectively suppressed in Ppm1k-deficient mice and can be restored with pharmacological activation of BCKA catabolism by BT2. Finally, hepatocytes lack branched-chain aminotransferase that alleviates BCKA accumulation via reversible conversion between BCAAs and BCKAs. This renders liver MPC most susceptible to circulating BCKA levels hence a sensor of BCAA catabolism.
    Keywords:  CP: Metabolism; branched-chain amino acids; branched-chain keto acids; gluconeogenesis; mitochondrial pyruvate carrier; pyruvate
    DOI:  https://doi.org/10.1016/j.celrep.2023.112641
  32. Methods Mol Biol. 2023 ;2683 103-111
    Characterizing the Neuron-Glial Interactions by the Co-cultures of Human iPSC-Derived Oligodendroglia and Neurons.
    Gabriella Vulakh, Xin Yang.
      Induced pluripotent stem cell (iPSC) techniques have had considerable breakthroughs in modeling human neurological diseases. Multiple protocols inducing neurons, astrocytes, microglia, oligodendrocytes, and endothelial cells have been well-established thus far. However, these protocols have limitations, including the long time period to get cells of interest or the challenge of culturing more than one cell type simultaneously. Protocols for handling multiple cell types within a shorter time period are still being established. Here we describe a simple and reliable co-culture system to study interactions between neurons and oligodendrocyte precursor cells (OPC) in health and in disease.
    Keywords:  Co-culture; Induced pluripotent stem (iPS) cells; Neuron-glial interactions; Neurons; Oligodendrocyte precursor cells
    DOI:  https://doi.org/10.1007/978-1-0716-3287-1_9
  33. BMC Bioinformatics. 2023 Jun 15. 24(1): 250
    Statistical methods and resources for biomarker discovery using metabolomics.
    Najeha R Anwardeen, Ilhame Diboun, Younes Mokrab, Asma A Althani, Mohamed A Elrayess.
      Metabolomics is a dynamic tool for elucidating biochemical changes in human health and disease. Metabolic profiles provide a close insight into physiological states and are highly volatile to genetic and environmental perturbations. Variation in metabolic profiles can inform mechanisms of pathology, providing potential biomarkers for diagnosis and assessment of the risk of contracting a disease. With the advancement of high-throughput technologies, large-scale metabolomics data sources have become abundant. As such, careful statistical analysis of intricate metabolomics data is essential for deriving relevant and robust results that can be deployed in real-life clinical settings. Multiple tools have been developed for both data analysis and interpretations. In this review, we survey statistical approaches and corresponding statistical tools that are available for discovery of biomarkers using metabolomics.
    Keywords:  Analytical workflow; Metabolomics; Metabolomics tools; Multivariate; Statistical methods; Univariate
    DOI:  https://doi.org/10.1186/s12859-023-05383-0
  34. J Transl Med. 2023 Jun 10. 21(1): 378
    Implementation of Nanopore sequencing as a pragmatic workflow for copy number variant confirmation in the clinic.
    Stephanie U Greer, Jacquelin Botello, Donna Hongo, Brynn Levy, Premal Shah, Matthew Rabinowitz, Danny E Miller, Kate Im, Akash Kumar.
       BACKGROUND: Diagnosis of rare genetic diseases can be a long, expensive and complex process, involving an array of tests in the hope of obtaining an actionable result. Long-read sequencing platforms offer the opportunity to make definitive molecular diagnoses using a single assay capable of detecting variants, characterizing methylation patterns, resolving complex rearrangements, and assigning findings to long-range haplotypes. Here, we demonstrate the clinical utility of Nanopore long-read sequencing by validating a confirmatory test for copy number variants (CNVs) in neurodevelopmental disorders and illustrate the broader applications of this platform to assess genomic features with significant clinical implications.
    METHODS: We used adaptive sampling on the Oxford Nanopore platform to sequence 25 genomic DNA samples and 5 blood samples collected from patients with known or false-positive copy number changes originally detected using short-read sequencing. Across the 30 samples (a total of 50 with replicates), we assayed 35 known unique CNVs (a total of 55 with replicates) and one false-positive CNV, ranging in size from 40 kb to 155 Mb, and assessed the presence or absence of suspected CNVs using normalized read depth.
    RESULTS: Across 50 samples (including replicates) sequenced on individual MinION flow cells, we achieved an average on-target mean depth of 9.5X and an average on-target read length of 4805 bp. Using a custom read depth-based analysis, we successfully confirmed the presence of all 55 known CNVs (including replicates) and the absence of one false-positive CNV. Using the same CNV-targeted data, we compared genotypes of single nucleotide variant loci to verify that no sample mix-ups occurred between assays. For one case, we also used methylation detection and phasing to investigate the parental origin of a 15q11.2-q13 duplication with implications for clinical prognosis.
    CONCLUSIONS: We present an assay that efficiently targets genomic regions to confirm clinically relevant CNVs with a concordance rate of 100%. Furthermore, we demonstrate how integration of genotype, methylation, and phasing data from the Nanopore sequencing platform can potentially simplify and shorten the diagnostic odyssey.
    Keywords:  Adaptive sampling; Clinical testing; Copy number variants; Genome analysis; Long-read sequencing; Neurodevelopmental disorders; Oxford Nanopore Technologies; Targeted sequencing
    DOI:  https://doi.org/10.1186/s12967-023-04243-y
  35. Int J Biol Sci. 2023 ;19(9): 2756-2771
    The crosstalk between ferroptosis and mitochondrial dynamic regulatory networks.
    Jie Li, Yu-Chen Jia, Yi-Xuan Ding, Jian Bai, Feng Cao, Fei Li.
      Ferroptosis is an iron-driven cell death modality characterized by iron accumulation and excessive lipid peroxidation. Ferroptosis is closely related to mitochondrial function, as indicated by studies showing that mitochondrial dysfunction and damage promote oxidative stress, which in turn induces ferroptosis. Mitochondria play crucial roles in cellular homeostasis, and abnormalities in their morphology and function are closely associated with the development of many diseases. Mitochondria are highly dynamic organelles, and their stability is maintained through a series of regulatory pathways. Mitochondrial homeostasis is dynamically regulated, mainly via key processes such as mitochondrial fission, mitochondrial fusion and mitophagy; however, mitochondrial processes are prone to dysregulation. Mitochondrial fission and fusion and mitophagy are intimately related to ferroptosis. Therefore, investigations into the dynamic regulation of mitochondrial processes during ferroptosis are important to provide a better understanding of the development of disease. In this paper, we systematically summarized changes in ferroptosis, mitochondrial fission and fusion and mitophagy to promote an in-depth understanding of the mechanism underlying ferroptosis and provide a corresponding reference for the treatment of related diseases.
    Keywords:  ferroptosis; mitochondrial fission; mitochondrial fusion; mitochondrial homeostasis; mitophagy; reactive oxygen species
    DOI:  https://doi.org/10.7150/ijbs.83348
  36. Neuropathol Appl Neurobiol. 2023 Jun 16. e12920
    Beyond vacuolar pathology: Multiomic profiling of Danon disease reveals dysfunctional mitochondrial homeostasis.
    Felix Kleefeld, Andreas Hentschel, Arpad von Moers, Katrin Hahn, Rita Horvath, Hans-Hilmar Goebel, Corinna Preusse, Jens Schallner, Markus Schuelke, Andreas Roos, Werner Stenzel.
      
    Keywords:  Danon disease; LAMP2; mitophagy; proteomics; transcriptomics
    DOI:  https://doi.org/10.1111/nan.12920
  37. Cells. 2023 May 25. pii: 1473. [Epub ahead of print]12(11):
    Mitochondrial Transfer to Host Cells from Ex Vivo Expanded Donor Hematopoietic Stem Cells.
    Hiroki Kawano, Yuko Kawano, Chen Yu, Mark W LaMere, Matthew J McArthur, Michael W Becker, Scott W Ballinger, Satoshi Gojo, Roman A Eliseev, Laura M Calvi.
      Mitochondrial dysfunction is observed in various conditions, from metabolic syndromes to mitochondrial diseases. Moreover, mitochondrial DNA (mtDNA) transfer is an emerging mechanism that enables the restoration of mitochondrial function in damaged cells. Hence, developing a technology that facilitates the transfer of mtDNA can be a promising strategy for the treatment of these conditions. Here, we utilized an ex vivo culture of mouse hematopoietic stem cells (HSCs) and succeeded in expanding the HSCs efficiently. Upon transplantation, sufficient donor HSC engraftment was attained in-host. To assess the mitochondrial transfer via donor HSCs, we used mitochondrial-nuclear exchange (MNX) mice with nuclei from C57BL/6J and mitochondria from the C3H/HeN strain. Cells from MNX mice have C57BL/6J immunophenotype and C3H/HeN mtDNA, which is known to confer a higher stress resistance to mitochondria. Ex vivo expanded MNX HSCs were transplanted into irradiated C57BL/6J mice and the analyses were performed at six weeks post transplantation. We observed high engraftment of the donor cells in the bone marrow. We also found that HSCs from the MNX mice could transfer mtDNA to the host cells. This work highlights the utility of ex vivo expanded HSC to achieve the mitochondrial transfer from donor to host in the transplant setting.
    Keywords:  MNX mouse, 5; ex vivo HSC expansion 3; in vivo mitochondrial transfer; mitochondrial DNA 2
    DOI:  https://doi.org/10.3390/cells12111473
  38. Front Nutr. 2023 ;10 964337
    Mitochondrial DNA methylation in metabolic associated fatty liver disease.
    Archibold Mposhi, Fabian Cortés-Mancera, Janette Heegsma, Vincent E de Meijer, Bart van de Sluis, Svenja Sydor, Lars P Bechmann, Claudia Theys, Peter de Rijk, Tim De Pooter, Wim Vanden Berghe, İkbal Agah İnce, Klaas Nico Faber, Marianne G Rots.
       Introduction: Hepatic lipid accumulation and mitochondrial dysfunction are hallmarks of metabolic associated fatty liver disease (MAFLD), yet molecular parameters underlying MAFLD progression are not well understood. Differential methylation within the mitochondrial DNA (mtDNA) has been suggested to be associated with dysfunctional mitochondria, also during progression to Metabolic Steatohepatitis (MeSH). This study further investigates whether mtDNA methylation is associated with hepatic lipid accumulation and MAFLD.
    Methods: HepG2 cells were constructed to stably express mitochondria-targeted viral and prokaryotic cytosine DNA methyltransferases (mtM.CviPI or mtM.SssI for GpC or CpG methylation, respectively). A catalytically inactive variant (mtM.CviPI-Mut) was constructed as a control. Mouse and human patients' samples were also investigated. mtDNA methylation was assessed by pyro- or nanopore sequencing.
    Results and discussion: Differentially induced mtDNA hypermethylation impaired mitochondrial gene expression and metabolic activity in HepG2-mtM.CviPI and HepG2-mtM.SssI cells and was associated with increased lipid accumulation, when compared to the controls. To test whether lipid accumulation causes mtDNA methylation, HepG2 cells were subjected to 1 or 2 weeks of fatty acid treatment, but no clear differences in mtDNA methylation were detected. In contrast, hepatic Nd6 mitochondrial gene body cytosine methylation and Nd6 gene expression were increased in mice fed a high-fat high cholesterol diet (HFC for 6 or 20 weeks), when compared to controls, while mtDNA content was unchanged. For patients with simple steatosis, a higher ND6 methylation was confirmed using Methylation Specific PCR, but no additional distinctive cytosines could be identified using pyrosequencing. This study warrants further investigation into a role for mtDNA methylation in promoting mitochondrial dysfunction and impaired lipid metabolism in MAFLD.
    Keywords:  NAFLD; NASH; ND6; liver steatosis; mtDNA methylation
    DOI:  https://doi.org/10.3389/fnut.2023.964337
  39. EMBO Rep. 2023 Jun 12. e56297
    MIRO-1 interacts with VDAC-1 to regulate mitochondrial membrane potential in Caenorhabditis elegans.
    Xuecong Ren, Hengda Zhou, Yujie Sun, Hongying Fu, Yu Ran, Bing Yang, Fan Yang, Mikael Bjorklund, Suhong Xu.
      Precise regulation of mitochondrial fusion and fission is essential for cellular activity and animal development. Imbalances between these processes can lead to fragmentation and loss of normal membrane potential in individual mitochondria. In this study, we show that MIRO-1 is stochastically elevated in individual fragmented mitochondria and is required for maintaining mitochondrial membrane potential. We further observe a higher level of membrane potential in fragmented mitochondria in fzo-1 mutants and wounded animals. Moreover, MIRO-1 interacts with VDAC-1, a crucial mitochondrial ion channel located in the outer mitochondrial membrane, and this interaction depends on the residues E473 of MIRO-1 and K163 of VDAC-1. The E473G point mutation disrupts their interaction, resulting in a reduction of the mitochondrial membrane potential. Our findings suggest that MIRO-1 regulates membrane potential and maintains mitochondrial activity and animal health by interacting with VDAC-1. This study provides insight into the mechanisms underlying the stochastic maintenance of membrane potential in fragmented mitochondria.
    Keywords:   Caenorhabditis elegans ; MIRO-1; VDAC-1; mitochondrial fragmentation; mitochondrial membrane potential (ΔΨm)
    DOI:  https://doi.org/10.15252/embr.202256297
  40. Proc Natl Acad Sci U S A. 2023 Jun 20. 120(25): e2300008120
    The mRNA translation initiation factor eIF4G1 controls mitochondrial oxidative phosphorylation, axonal morphogenesis, and memory.
    Sung-Hoon Kim, Jung-Hyun Choi, Laura Marsal-García, Mehdi Amiri, Akiko Yanagiya, Nahum Sonenberg.
      mRNA translation initiation plays a critical role in learning and memory. The eIF4F complex, composed of the cap-binding protein eIF4E, ATP-dependent RNA helicase eIF4A, and scaffolding protein eIF4G, is a pivotal factor in the mRNA translation initiation process. eIF4G1, the major paralogue of the three eIF4G family members, is indispensable for development, but its function in learning and memory is unknown. To study the role of eIF4G1 in cognition, we used an eIF4G1 haploinsufficient (eIF4G1-1D) mouse model. The axonal arborization of eIF4G1-1D primary hippocampal neurons was significantly disrupted, and the mice displayed impairment in hippocampus-dependent learning and memory. Translatome analysis showed that the translation of mRNAs encoding proteins of the mitochondrial oxidative phosphorylation (OXPHOS) system was decreased in the eIF4G1-1D brain, and OXPHOS was decreased in eIF4G1-silenced cells. Thus, eIF4G1-mediated mRNA translation is crucial for optimal cognitive function, which is dependent on OXPHOS and neuronal morphogenesis.
    Keywords:  learning and memory; mitochondria; neuronal morphogenesis; oxidative phosphorylation; translational control
    DOI:  https://doi.org/10.1073/pnas.2300008120
  41. Curr Drug Metab. 2023 Jun 14.
    The application of nucleic acid nanomaterials in the treatment of mitochondrial dysfunction.
    Lan Yao, Hai Qing, Tao Zhang.
      Mitochondrial dysfunction is considered highly related to the development and progression of diseases, including cancer, metabolism disturbance, and neurodegeneration. Traditional pharmacological approach for mitochondrial dysfunction treatment has off-target and dose-dependent side effects, which leads to the emergence of mitochondrial gene therapy by regulating coding or noncoding genes by using nucleic acid sequences such as oligonucleotides, peptide nucleic acids, rRNA, siRNA, etc. To avoid size heterogeneity and potential cytotoxicity of the traditional delivery vehicle like liposome, framework nucleic acids have shown promising potentials. First, special spatial structure like tetrahedron allows entry into cells without transfection reagents. Second, the nature of nucleic acid provides the editability of framework structure, more sites and methods for drug loading and targeted sequences linking, providing efficient transportation and accurate targeting to mitochondria. Third, controllable size leads a possibility to go through biological barrier such as the blood-brain barrier, reaching the central nervous system to reverse mitochondria-related neurodegeneration. In addition, it's biocompatibility and physiological environmental stability open up the possibility of in vivo treatments for mitochondrial dysfunction. Furthermore, we discuss the challenges and opportunities of framework nucleic acids-based delivery systems in mitochondrial dysfunction.
    Keywords:  Drug delivery; Framework nucleic acid; Mitochondrial dysfunction; Mitochondrial targeting; Nanomaterials; Nucleic acid drugs
    DOI:  https://doi.org/10.2174/1389200224666230614115655
  42. Sci Immunol. 2023 Jun 23. 8(84): eade7652
    Hexokinase dissociation from mitochondria promotes oligomerization of VDAC that facilitates NLRP3 inflammasome assembly and activation.
    Sung Hoon Baik, V Krishnan Ramanujan, Courtney Becker, Sarah Fett, David M Underhill, Andrea J Wolf.
      NLRP3 inflammasome activation is a highly regulated process for controlling secretion of the potent inflammatory cytokines IL-1β and IL-18 that are essential during bacterial infection, sterile inflammation, and disease, including colitis, diabetes, Alzheimer's disease, and atherosclerosis. Diverse stimuli activate the NLRP3 inflammasome, and unifying upstream signals has been challenging to identify. Here, we report that a common upstream step in NLRP3 inflammasome activation is the dissociation of the glycolytic enzyme hexokinase 2 from the voltage-dependent anion channel (VDAC) in the outer membrane of mitochondria. Hexokinase 2 dissociation from VDAC triggers activation of inositol triphosphate receptors, leading to release of calcium from the ER, which is taken up by mitochondria. This influx of calcium into mitochondria leads to oligomerization of VDAC, which is known to form a macromolecule-sized pore in the outer membranes of mitochondria that allows proteins and mitochondrial DNA (mtDNA), often associated with apoptosis and inflammation, respectively, to exit the mitochondria. We observe that VDAC oligomers aggregate with NLRP3 during initial assembly of the multiprotein oligomeric NLRP3 inflammasome complex. We also find that mtDNA is necessary for NLRP3 association with VDAC oligomers. These data, together with other recent work, help to paint a more complete picture of the pathway leading to NLRP3 inflammasome activation.
    DOI:  https://doi.org/10.1126/sciimmunol.ade7652
  43. Eur J Neurosci. 2023 Jun 16.
    Spinocerebellar ataxia type 11 (SCA11): An update.
    Ziwei Gong, Lifang Lei.
      Spinocerebellar ataxias, also called autosomal dominant cerebellar ataxias, are a group of neurological genetic diseases characterised by chronic, progressive cerebellar ataxia. The clinical hallmark of spinocerebellar ataxia is the loss of balance and coordination, accompanied by slurred speech. Spinocerebellar ataxia type 11 is a rare subtype of spinocerebellar ataxia caused by mutations in the tau tubulin kinase 2 gene. Patients with spinocerebellar ataxia are clinically characterised by slowly progressive cerebellar ataxia, trunk and limb ataxia, and eye movement abnormalities with occasional pyramidal features. Peripheral neuropathy and dystonia are rare. According to the literature, only nine families affected with spinocerebellar ataxia have been reported worldwide. Herein, a series of spinocerebellar ataxia cases are discussed in detail to determine the potential research direction of this dysfunction, including its epidemiology, clinical features, genetic characteristics, diagnosis and differential diagnosis, pathogenic mechanisms, treatment, prognosis, follow-up, genetic counselling and future perspectives, and to improve the overall understanding of spinocerebellar ataxia among clinicians, researchers and patients.
    Keywords:  TTBK2; clinical symptoms; genetic characteristics; pathogenic mechanisms; spinocerebellar ataxia type 11
    DOI:  https://doi.org/10.1111/ejn.16054
  44. Antioxid Redox Signal. 2023 Jun 10.
    NAD DEFICIENCY AND ITS IMPACT ON MAMMALIAN DEVELOPMENT.
    Sally Dunwoodie, Kayleigh Bozon, Justin Szot, Hartmut Cuny.
       SIGNIFICANCE: NAD is an important molecule synthesised from tryptophan or vitamin B3 and involved in numerous cellular reactions. NAD deficiency during pregnancy causes Congenital NAD Deficiency Disorder (CNDD) characterised by multiple congenital malformations and/or miscarriage. Studies in genetically engineered mice replicating mutations found in human patient cases show that CNDD can be prevented by dietary supplements.
    RECENT ADVANCES: A growing number of patient reports show that biallelic loss-of-function of genes involved in NAD de novo synthesis (KYNU, HAAO, NADSYN1) cause CNDD. Other factors that limit the availability of NAD precursors, e.g. limited dietary precursor supply or absorption, can cause or contribute to NAD deficiency and result in CNDD in mice. Molecular flux experiments allow quantitative understanding of NAD precursor concentrations in the circulation and their usage by different cells. Studies of NAD-consuming enzymes and contributors to NAD homeostasis help better understand how perturbed NAD levels are implicated in various diseases and adverse pregnancy outcomes.
    CRITICAL ISSUES: NAD deficiency is one of the many known causes of adverse pregnancy outcomes, but its prevalence in the human population and among pregnant women is unknown. Since NAD is involved in hundreds of diverse cellular reactions, determining how NAD deficiency disrupts embryogenesis is an important challenge.
    FUTURE DIRECTIONS: Furthering our understanding of the molecular fluxes between the maternal and embryonic circulation during pregnancy, the NAD-dependent pathways active in the developing embryo, and the molecular mechanisms by which NAD deficiency causes adverse pregnancy outcomes will provide direction for future prevention strategies.
    DOI:  https://doi.org/10.1089/ars.2023.0349
  45. Circ Res. 2023 Jun 15.
    iPSC-Based Modeling of Variable Clinical Presentation in Hypertrophic Cardiomyopathy.
    Rubén Escribá, José M Larrañaga-Moreira, Yvonne Richaud-Patin, Léa Pourchet, Ioannis Lazis, Senda Jiménez-Delgado, Alba Morillas-García, Martín Ortiz-Genga, Juan Pablo Ochoa, David Carreras, Guillermo Javier Pérez, José Luis de la Pompa, Ramón Brugada, Lorenzo Monserrat, Roberto Barriales-Villa, Angel Raya.
       BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease and a frequent cause of heart failure and sudden cardiac death. Our understanding of the genetic bases and pathogenic mechanisms underlying HCM has improved significantly in the recent past, but the combined effect of various pathogenic gene variants and the influence of genetic modifiers in disease manifestation are very poorly understood. Here, we set out to investigate genotype-phenotype relationships in 2 siblings with an extensive family history of HCM, both carrying a pathogenic truncating variant in the MYBPC3 gene (p.Lys600Asnfs*2), but who exhibited highly divergent clinical manifestations.
    METHODS AND RESULTS: We used a combination of induced pluripotent stem cell (iPSC)-based disease modeling and CRISPR/Cas9-mediated genome editing to generate patient-specific cardiomyocytes (iPSC-CMs) and isogenic controls lacking the pathogenic MYBPC3 variant. Mutant iPSC-CMs developed impaired mitochondrial bioenergetics, which was dependent on the presence of the mutation. Moreover, we could detect altered excitation-contraction coupling in iPSC-CMs from the severely affected individual. The pathogenic MYBPC3 variant was found to be necessary, but not sufficient, to induce iPSC-CM hyperexcitability, suggesting the presence of additional genetic modifiers. Whole-exome sequencing of the mutant carriers identified a variant of unknown significance in the MYH7 gene (p.Ile1927Phe) uniquely present in the individual with severe HCM. We finally assessed the pathogenicity of this variant of unknown significance by functionally evaluating iPSC-CMs after editing the variant.
    CONCLUSIONS: Our results indicate that the p.Ile1927Phe variant of unknown significance in MYH7 can be considered as a modifier of HCM expressivity when found in combination with truncating variants in MYBPC3. Overall, our studies show that iPSC-based modeling of clinically discordant subjects provides a unique platform to functionally assess the effect of genetic modifiers.
    Keywords:  energy metabolism; mutation; phenotype; sibling; studies
    DOI:  https://doi.org/10.1161/CIRCRESAHA.122.321951
  46. Neurobiol Dis. 2023 Jun 13. pii: S0969-9961(23)00214-0. [Epub ahead of print] 106199
    Brightness and shadows of mitochondrial ROS in the brain.
    Daniel Jimenez-Blasco, Angeles Almeida, Juan P Bolaños.
      Mitochondrial reactive oxygen species (mROS) have been generally considered harmful byproducts wanted to clear when elevated to avoid brain damage. However, the abundance of mROS in astrocytes is very high -about one order of magnitude above that in neurons-, despite they are essential to preserve cell metabolism and animal behavior. Here, we have focused on this apparent ambiguity by discussing (i) the intrinsic mechanisms accounting for the higher production of mROS by the mitochondrial respiratory chain in astrocytes than in neurons, (ii) the specific molecular targets of astrocytic beneficial mROS, and (iii) how decreased astrocytic mROS causes excess neuronal mROS leading to cellular and organismal damage. We hope that this mini-review serves to clarifying the apparent controversy on the beneficial versus deleterious faces of ROS in the brain from molecular to higher-order organismal levels.
    Keywords:  Astrocytes; Glutathione; Mitochondria; Neurons; Reactive oxygen species; Supercomplexes
    DOI:  https://doi.org/10.1016/j.nbd.2023.106199
  47. Exploration (Beijing). 2021 Dec;1(3): 20210115
    Mitochondria-targeted nanoparticles in treatment of neurodegenerative diseases.
    Yue Zhang, Han Yang, Daohe Wei, Xinhui Zhang, Jian Wang, Xiaoli Wu, Jin Chang.
      Neurodegenerative diseases (NDs) are a class of heterogeneous diseases that includes Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Mitochondria play an important role in oxidative balance and metabolic activity of neurons; therefore, mitochondrial dysfunction is associated with NDs and mitochondria are considered a potential treatment target for NDs. Several obstacles, including the blood-brain barrier (BBB) and cell/mitochondrial membranes, reduce the efficiency of drug entry into the target lesions. Therefore, a variety of neuron mitochondrial targeting strategies has been developed. Among them, nanotechnology-based treatments show especially promising results. Owing to their adjustable size, appropriate charge, and lipophilic surface, nanoparticles (NPs) are the ideal theranostic system for crossing the BBB and targeting the neuronal mitochondria. In this review, we discussed the role of dysfunctional mitochondria in ND pathogenesis as well as the physiological barriers to various treatment strategies. We also reviewed the use and advantages of various NPs (including organic, inorganic, and biological membrane-coated NPs) for the treatment and diagnosis of NDs. Finally, we summarized the evidence and possible use for the promising role of NP-based theranostic systems in the treatment of mitochondrial dysfunction-related NDs.
    Keywords:  mitochondrial dysfunction; nanoparticles; neurodegenerative diseases; oxidative stress; target
    DOI:  https://doi.org/10.1002/EXP.20210115
  48. Genes Chromosomes Cancer. 2023 Jun 14.
    Machine learning in computational histopathology: Challenges and opportunities.
    Michael Cooper, Zongliang Ji, Rahul G Krishnan.
      Digital histopathological images, high-resolution images of stained tissue samples, are a vital tool for clinicians to diagnose and stage cancers. The visual analysis of patient state based on these images are an important part of oncology workflow. Although pathology workflows have historically been conducted in laboratories under a microscope, the increasing digitization of histopathological images has led to their analysis on computers in the clinic. The last decade has seen the emergence of machine learning, and deep learning in particular, a powerful set of tools for the analysis of histopathological images. Machine learning models trained on large datasets of digitized histopathology slides have resulted in automated models for prediction and stratification of patient risk. In this review, we provide context for the rise of such models in computational histopathology, highlight the clinical tasks they have found success in automating, discuss the various machine learning techniques that have been applied to this domain, and underscore open problems and opportunities.
    Keywords:  computational pathology; deep learning; machine learning
    DOI:  https://doi.org/10.1002/gcc.23177
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