bims-midmar Biomed News
on Mitochondrial DNA maintenance and replication
Issue of 2021‒10‒17
eighteen papers selected by
Flavia Söllner
Ludwig-Maximilians University
  1. Generating stable isolated mitochondrial recipient clones in mammalian cells using MitoPunch mitochondrial transfer.
  2. The population frequency of human mitochondrial DNA variants is highly dependent upon mutational bias.
  3. Nanopore Single-Molecule Sequencing for Mitochondrial DNA Methylation Analysis: Investigating Parkin-Associated Parkinsonism as a Proof of Concept.
  4. Age-related mitochondrial alterations in brain and skeletal muscle of the YAC128 model of Huntington disease.
  5. Downregulation of mitochondrial biogenesis by virus infection triggers antiviral responses by cyclic GMP-AMP synthase.
  6. Ancient Mitochondrial Genomes Reveal Extensive Genetic Influence of the Steppe Pastoralists in Western Xinjiang.
  7. A benchmarking of human mitochondrial DNA haplogroup classifiers from whole-genome and whole-exome sequence data.
  8. Polyphosphate-dependent nicotinamide adenine dinucleotide (NAD) kinase: A novel missing link in human mitochondria.
  9. Clinical, imaging, biochemical and molecular features in Leigh syndrome: a study from the Italian network of mitochondrial diseases.
  10. A Method to Monitor the NAD+ Metabolome-From Mechanistic to Clinical Applications.
  11. Resveratrol enhanced mitochondrial recovery from cryopreservation-induced damages in oocytes and embryos.
  12. A recessive variant in TFAM causes mtDNA depletion associated with primary ovarian insufficiency, seizures, intellectual disability and hearing loss.
  13. Nicotinamide Riboside and Metformin Ameliorate Mitophagy Defect in Induced Pluripotent Stem Cell-Derived Astrocytes With POLG Mutations.
  14. Hierarchical folding of the catalytic core during mitochondrial ribosome biogenesis.
  15. Reversible and irreversible mitochondrial swelling: Effects of variable mitochondrial activity.
  16. Characterisation of Plasma Mitochondrial DNA, MMP-9 and Neutrophil Elastase in Patients Undergoing Coronary Artery Bypass Grafting: Effects of Tranexamic Acid and Postoperative Pneumonia.
  17. Emerging perspectives on mitochondrial dysfunctioning and inflammation in epileptogenesis.
  18. Mitochondrial Ca2+-overloading by oxygen/glutathione depletion-boosted photodynamic therapy based on a CaCO3 nanoplatform for tumor synergistic therapy.
  1. STAR Protoc. 2021 Dec 17. 2(4): 100850
    Generating stable isolated mitochondrial recipient clones in mammalian cells using MitoPunch mitochondrial transfer.
    Alexander J Sercel, Alexander J Napior, Alexander N Patananan, Ting-Hsiang Wu, Pei-Yu Chiou, Michael A Teitell.
      This protocol describes the assembly and use of MitoPunch to deliver mitochondria containing mitochondrial DNA (mtDNA) into cells lacking mtDNA (ρ0 cells). MitoPunch generates stable isolated mitochondrial recipient clones with restored mtDNA and recovered respiration, enabling investigation of mtDNA mutations and mtDNA-nuclear DNA interactions in a range of cell types. For complete details on the use and execution of this protocol, please refer to Sercel et al. (2021) and Patananan et al. (2020).
    Keywords:  Biotechnology and bioengineering; Cell Biology; Cell culture; Cell-based Assays; Metabolism
    DOI:  https://doi.org/10.1016/j.xpro.2021.100850
  2. Biol Open. 2021 Oct 13. pii: bio.059072. [Epub ahead of print]
    The population frequency of human mitochondrial DNA variants is highly dependent upon mutational bias.
    Cory D Dunn.
      Next-generation sequencing can quickly reveal genetic variation potentially linked to heritable disease. As databases encompassing human variation continue to expand, rare variants have been of high interest, since the frequency of a variant is expected to be low if the genetic change leads to a loss of fitness or fecundity. However, the use of variant frequency when seeking genomic changes linked to disease remains very challenging. Here, we explore the role of selection in controlling human variant frequency using the HelixMT database, which encompasses hundreds of thousands of mitochondrial DNA (mtDNA) samples. We find that a substantial number of synonymous substitutions, which have no effect on protein sequence, were never encountered in this large study, while many other synonymous changes are found at very low frequencies. Further analyses of human and mammalian mtDNA datasets indicate that the population frequency of synonymous variants is predominantly determined by mutational biases rather than by strong selection acting upon nucleotide choice. Our work has important implications that extend to the interpretation of variant frequency for non-synonymous substitutions.
    Keywords:  Genomic variation; Mitochondrial DNA; Mutational bias; Pathogenicity prediction; Population frequency
    DOI:  https://doi.org/10.1242/bio.059072
  3. Front Aging Neurosci. 2021 ;13 713084
    Nanopore Single-Molecule Sequencing for Mitochondrial DNA Methylation Analysis: Investigating Parkin-Associated Parkinsonism as a Proof of Concept.
    Theresa Lüth, Kobi Wasner, Christine Klein, Susen Schaake, Ronnie Tse, Sandro L Pereira, Joshua Laß, Lasse Sinkkonen, Anne Grünewald, Joanne Trinh.
      Objective: To establish a workflow for mitochondrial DNA (mtDNA) CpG methylation using Nanopore whole-genome sequencing and perform first pilot experiments on affected Parkin biallelic mutation carriers (Parkin-PD) and healthy controls. Background: Mitochondria, including mtDNA, are established key players in Parkinson's disease (PD) pathogenesis. Mutations in Parkin, essential for degradation of damaged mitochondria, cause early-onset PD. However, mtDNA methylation and its implication in PD is understudied. Herein, we establish a workflow using Nanopore sequencing to directly detect mtDNA CpG methylation and compare mtDNA methylation between Parkin-related PD and healthy individuals. Methods: To obtain mtDNA, whole-genome Nanopore sequencing was performed on blood-derived from five Parkin-PD and three control subjects. In addition, induced pluripotent stem cell (iPSC)-derived midbrain neurons from four of these patients with PD and the three control subjects were investigated. The workflow was validated, using methylated and unmethylated 897 bp synthetic DNA samples at different dilution ratios (0, 50, 100% methylation) and mtDNA without methylation. MtDNA CpG methylation frequency (MF) was detected using Nanopolish and Megalodon. Results: Across all blood-derived samples, we obtained a mean coverage of 250.3X (SD ± 80.5X) and across all neuron-derived samples 830X (SD ± 465X) of the mitochondrial genome. We detected overall low-level CpG methylation from the blood-derived DNA (mean MF ± SD = 0.029 ± 0.041) and neuron-derived DNA (mean MF ± SD = 0.019 ± 0.035). Validation of the workflow, using synthetic DNA samples showed that highly methylated DNA molecules were prone to lower Guppy Phred quality scores and thereby more likely to fail Guppy base-calling. CpG methylation in blood- and neuron-derived DNA was significantly lower in Parkin-PD compared to controls (Mann-Whitney U-test p < 0.05). Conclusion: Nanopore sequencing is a useful method to investigate mtDNA methylation architecture, including Guppy-failed reads is of importance when investigating highly methylated sites. We present a mtDNA methylation workflow and suggest methylation variability across different tissues and between Parkin-PD patients and controls as an initial model to investigate.
    Keywords:  Nanopore; Parkin; Parkinson's disease; methylation; mitochondrial DNA; third-generation sequencing
    DOI:  https://doi.org/10.3389/fnagi.2021.713084
  4. NPJ Aging Mech Dis. 2021 Oct 14. 7(1): 26
    Age-related mitochondrial alterations in brain and skeletal muscle of the YAC128 model of Huntington disease.
    Kristina Bečanović, Asghar Muhammad, Izabella Gadawska, Shiny Sachdeva, David Walker, Eduardo R Lazarowski, Sonia Franciosi, Kevin H J Park, Hélène C F Côté, Blair R Leavitt.
      Mitochondrial dysfunction and bioenergetics failure are common pathological hallmarks in Huntington's disease (HD) and aging. In the present study, we used the YAC128 murine model of HD to examine the effects of mutant huntingtin on mitochondrial parameters related to aging in brain and skeletal muscle. We have conducted a cross-sectional natural history study of mitochondrial DNA changes in the YAC128 mouse. Here, we first show that the mitochondrial volume fraction appears to increase in the axons and dendrite regions adjacent to the striatal neuron cell bodies in old mice. Mitochondrial DNA copy number (mtDNAcn) was used as a proxy measure for mitochondrial biogenesis and function. We observed that the mtDNAcn changes significantly with age and genotype in a tissue-specific manner. We found a positive correlation between aging and the mtDNAcn in striatum and skeletal muscle but not in cortex. Notably, the YAC128 mice had lower mtDNAcn in cortex and skeletal muscle. We further show that mtDNA deletions are present in striatal and skeletal muscle tissue in both young and aged YAC128 and WT mice. Tracking gene expression levels cross-sectionally in mice allowed us to identify contributions of age and genotype to transcriptional variance in mitochondria-related genes. These findings provide insights into the role of mitochondrial dynamics in HD pathogenesis in both brain and skeletal muscle, and suggest that mtDNAcn in skeletal muscle tissue may be a potential biomarker that should be investigated further in human HD.
    DOI:  https://doi.org/10.1038/s41514-021-00079-2
  5. PLoS Pathog. 2021 Oct;17(10): e1009841
    Downregulation of mitochondrial biogenesis by virus infection triggers antiviral responses by cyclic GMP-AMP synthase.
    Hiroki Sato, Miho Hoshi, Fusako Ikeda, Tomoko Fujiyuki, Misako Yoneda, Chieko Kai.
      In general, in mammalian cells, cytosolic DNA viruses are sensed by cyclic GMP-AMP synthase (cGAS), and RNA viruses are recognized by retinoic acid-inducible gene I (RIG-I)-like receptors, triggering a series of downstream innate antiviral signaling steps in the host. We previously reported that measles virus (MeV), which possesses an RNA genome, induces rapid antiviral responses, followed by comprehensive downregulation of host gene expression in epithelial cells. Interestingly, gene ontology analysis indicated that genes encoding mitochondrial proteins are enriched among the list of downregulated genes. To evaluate mitochondrial stress after MeV infection, we first observed the mitochondrial morphology of infected cells and found that significantly elongated mitochondrial networks with a hyperfused phenotype were formed. In addition, an increased amount of mitochondrial DNA (mtDNA) in the cytosol was detected during progression of infection. Based on these results, we show that cytosolic mtDNA released from hyperfused mitochondria during MeV infection is captured by cGAS and causes consequent priming of the DNA sensing pathway in addition to canonical RNA sensing. We also ascertained the contribution of cGAS to the in vivo pathogenicity of MeV. In addition, we found that other viruses that induce downregulation of mitochondrial biogenesis as seen for MeV cause similar mitochondrial hyperfusion and cytosolic mtDNA-priming antiviral responses. These findings indicate that the mtDNA-activated cGAS pathway is critical for full innate control of certain viruses, including RNA viruses that cause mitochondrial stress.
    DOI:  https://doi.org/10.1371/journal.ppat.1009841
  6. Front Genet. 2021 ;12 740167
    Ancient Mitochondrial Genomes Reveal Extensive Genetic Influence of the Steppe Pastoralists in Western Xinjiang.
    Chao Ning, Hong-Xiang Zheng, Fan Zhang, Sihao Wu, Chunxiang Li, Yongbin Zhao, Yang Xu, Dong Wei, Yong Wu, Shizhu Gao, Li Jin, Yinqiu Cui.
      The population prehistory of Xinjiang has been a hot topic among geneticists, linguists, and archaeologists. Current ancient DNA studies in Xinjiang exclusively suggest an admixture model for the populations in Xinjiang since the early Bronze Age. However, almost all of these studies focused on the northern and eastern parts of Xinjiang; the prehistoric demographic processes that occurred in western Xinjiang have been seldomly reported. By analyzing complete mitochondrial sequences from the Xiabandi (XBD) cemetery (3,500-3,300 BP), the up-to-date earliest cemetery excavated in western Xinjiang, we show that all the XBD mitochondrial sequences fall within two different West Eurasian mitochondrial DNA (mtDNA) pools, indicating that the migrants into western Xinjiang from west Eurasians were a consequence of the early expansion of the middle and late Bronze Age steppe pastoralists (Steppe_MLBA), admixed with the indigenous populations from Central Asia. Our study provides genetic links for an early existence of the Indo-Iranian language in southwestern Xinjiang and suggests that the existence of Andronovo culture in western Xinjiang involved not only the dispersal of ideas but also population movement.
    Keywords:  Andronovo; Eurasian Steppe; Silk Road; ancient DNA; mitochondrial genome
    DOI:  https://doi.org/10.3389/fgene.2021.740167
  7. Sci Rep. 2021 Oct 15. 11(1): 20510
    A benchmarking of human mitochondrial DNA haplogroup classifiers from whole-genome and whole-exome sequence data.
    Víctor García-Olivares, Adrián Muñoz-Barrera, José M Lorenzo-Salazar, Carlos Zaragoza-Trello, Luis A Rubio-Rodríguez, Ana Díaz-de Usera, David Jáspez, Antonio Iñigo-Campos, Rafaela González-Montelongo, Carlos Flores.
      The mitochondrial genome (mtDNA) is of interest for a range of fields including evolutionary, forensic, and medical genetics. Human mitogenomes can be classified into evolutionary related haplogroups that provide ancestral information and pedigree relationships. Because of this and the advent of high-throughput sequencing (HTS) technology, there is a diversity of bioinformatic tools for haplogroup classification. We present a benchmarking of the 11 most salient tools for human mtDNA classification using empirical whole-genome (WGS) and whole-exome (WES) short-read sequencing data from 36 unrelated donors. We also assessed the best performing tool in third-generation long noisy read WGS data obtained with nanopore technology for a subset of the donors. We found that, for short-read WGS, most of the tools exhibit high accuracy for haplogroup classification irrespective of the input file used for the analysis. However, for short-read WES, Haplocheck and MixEmt were the most accurate tools. Based on the performance shown for WGS and WES, and the accompanying qualitative assessment, Haplocheck stands out as the most complete tool. For third-generation HTS data, we also showed that Haplocheck was able to accurately retrieve mtDNA haplogroups for all samples assessed, although only after following assembly-based approaches (either based on a referenced-based assembly or a hybrid de novo assembly). Taken together, our results provide guidance for researchers to select the most suitable tool to conduct the mtDNA analyses from HTS data.
    DOI:  https://doi.org/10.1038/s41598-021-99895-5
  8. Proc Jpn Acad Ser B Phys Biol Sci. 2021 ;97(8): 479-498
    Polyphosphate-dependent nicotinamide adenine dinucleotide (NAD) kinase: A novel missing link in human mitochondria.
    Kousaku Murata.
      Polyphosphate [poly(P)] is described as a homopolymer of inorganic phosphates. Nicotinamide adenine dinucleotide kinase (NAD kinase) catalyzes the phosphorylation of NAD+ to NADP+ in the presence of ATP (ATP-NAD kinase). Novel NAD kinase that explicitly phosphorylates NAD+ to NADP+ using poly(P), besides ATP [ATP/poly(P)-NAD kinase], was found in bacteria, in particular, Gram-positive bacteria, and the gene encoding ATP/poly(P)-NAD kinase was also newly identified in Mycobacterium tuberculosis H37Rv. Both NAD kinases required multi-homopolymeric structures for activity expression. The enzymatic and genetic results, combined with their primary and tertiary structures, have led to the discovery of a long-awaited human mitochondrial NAD kinase. This discovery showed that the NAD kinase is a bacterial type of ATP/poly(P)-NAD kinase. These pioneering findings, i.e., ATP/poly(P)-NAD kinase, NAD kinase gene, and human mitochondrial NAD kinase, have significantly enhanced research on the biochemistry, molecular biology, and evolutionary biology of NAD kinase, mitochondria, and poly(P), including some biotechnological knowledge applicable to NADP+ production.
    Keywords:  NAD kinase; NAD kinase gene; NAD+; NADP+; human mitochondrial NAD kinase; polyphosphate
    DOI:  https://doi.org/10.2183/pjab.97.024
  9. Orphanet J Rare Dis. 2021 Oct 09. 16(1): 413
    Clinical, imaging, biochemical and molecular features in Leigh syndrome: a study from the Italian network of mitochondrial diseases.
    Anna Ardissone, Claudio Bruno, Daria Diodato, Alice Donati, Daniele Ghezzi, Eleonora Lamantea, Costanza Lamperti, Michelangelo Mancuso, Diego Martinelli, Guido Primiano, Elena Procopio, Anna Rubegni, Filippo Santorelli, Maria Cristina Schiaffino, Serenella Servidei, Flavia Tubili, Enrico Bertini, Isabella Moroni.
      BACKGROUND: Leigh syndrome (LS) is a progressive neurodegenerative disorder associated with primary or secondary dysfunction of mitochondrial oxidative phosphorylation and is the most common mitochondrial disease in childhood. Numerous reports on the biochemical and molecular profiles of LS have been published, but there are limited studies on genetically confirmed large series. We reviewed the clinical, imaging, biochemical and molecular data of 122 patients with a diagnosis of LS collected in the Italian Collaborative Network of Mitochondrial Diseases database.RESULTS: Clinical picture was characterized by early onset of several neurological signs dominated by central nervous system involvement associated with both supra- and sub-tentorial grey matter at MRI in the majority of cases. Extraneurological organ involvement is less frequent in LS than expected for a mitochondrial disorder. Complex I and IV deficiencies were the most common biochemical diagnoses, mostly associated with mutations in SURF1 or mitochondrial-DNA genes encoding complex I subunits. Our data showed SURF1 as the genotype with the most unfavorable prognosis, differently from other cohorts reported to date.
    CONCLUSION: We report on a large genetically defined LS cohort, adding new data on phenotype-genotype correlation, prognostic factors and possible suggestions to diagnostic workup.
    Keywords:  Basal ganglia; Childhood; Leigh syndrome; Mitochondrial disease
    DOI:  https://doi.org/10.1186/s13023-021-02029-3
  10. Int J Mol Sci. 2021 Sep 30. pii: 10598. [Epub ahead of print]22(19):
    A Method to Monitor the NAD+ Metabolome-From Mechanistic to Clinical Applications.
    Maria Pilar Giner, Stefan Christen, Simona Bartova, Mikhail V Makarov, Marie E Migaud, Carles Canto, Sofia Moco.
      Nicotinamide adenine dinucleotide (NAD+) and its reduced form (NADH) are coenzymes employed in hundreds of metabolic reactions. NAD+ also serves as a substrate for enzymes such as sirtuins, poly(ADP-ribose) polymerases (PARPs) and ADP-ribosyl cyclases. Given the pivotal role of NAD(H) in health and disease, studying NAD+ metabolism has become essential to monitor genetic- and/or drug-induced perturbations related to metabolic status and diseases (such as ageing, cancer or obesity), and its possible therapies. Here, we present a strategy based on liquid chromatography-tandem mass spectrometry (LC-MS/MS), for the analysis of the NAD+ metabolome in biological samples. In this method, hydrophilic interaction chromatography (HILIC) was used to separate a total of 18 metabolites belonging to pathways leading to NAD+ biosynthesis, including precursors, intermediates and catabolites. As redox cofactors are known for their instability, a sample preparation procedure was developed to handle a variety of biological matrices: cell models, rodent tissues and biofluids, as well as human biofluids (urine, plasma, serum, whole blood). For clinical applications, quantitative LC-MS/MS for a subset of metabolites was demonstrated for the analysis of the human whole blood of nine volunteers. Using this developed workflow, our methodology allows studying NAD+ biology from mechanistic to clinical applications.
    Keywords:  NAD+; mass spectrometry; metabolomics
    DOI:  https://doi.org/10.3390/ijms221910598
  11. Reprod Med Biol. 2021 Oct;20(4): 419-426
    Resveratrol enhanced mitochondrial recovery from cryopreservation-induced damages in oocytes and embryos.
    Hisataka Iwata.
      Background: Mitochondria play a crucial role in nuclear maturation, fertilization, and subsequent embryo development. Cryopreservation is an important assisted reproductive technology that is used worldwide for humans and domestic animals. Although mitochondrial quantity and quality are decisive factors for successful development of oocytes and embryos, cryopreservation induces mitochondrial dysfunction. Upon thawing, the damaged mitochondria are removed, and de novo synthesis occurs to restore the function of mitochondria. Resveratrol, 3,5,4'-trihydroxystilbene, is a polyphenolic antioxidant that has versatile target proteins, among which sirtuin-1 (SIRT1) is a key regulator of in mitochondrial biogenesis and degradation.Methods: The present study is a literature review focusing on experiments involving the hypothesis that the activation of mitochondrial biogenesis and degradation following cryopreservation and warming by resveratrol may help mitochondrial recovery and improve oocyte and embryo development.
    Main findings and conclusion: Resveratrol improves oocyte maturation and development and upregulates mitochondrial biogenesis and degradation. When vitrified-warmed embryos are treated with resveratrol, it helps in mitochondrial regulation and recovery of embryos from cryopreservation-induced damage.
    Conclusion: Resveratrol treatment is a possible countermeasure against cryopreservation-induced mitochondrial damage.
    Keywords:  SIRT1; cryopreservation; mitochondria; resveratrol
    DOI:  https://doi.org/10.1002/rmb2.12401
  12. Hum Genet. 2021 Oct 13.
    A recessive variant in TFAM causes mtDNA depletion associated with primary ovarian insufficiency, seizures, intellectual disability and hearing loss.
    Farid Ullah, Waqar Rauf, Kamal Khan, Sheraz Khan, Katrina M Bell, Vanessa Cristina de Oliveira, Muhammad Tariq, Shabnam Bakhshalizadeh, Philippe Touraine, Nicholas Katsanis, Andrew Sinclair, Sijie He, Elena J Tucker, Shahid M Baig, Erica E Davis.
      Mitochondrial disorders are collectively common, genetically heterogeneous disorders in both pediatric and adult populations. They are caused by molecular defects in oxidative phosphorylation, failure of essential bioenergetic supply to mitochondria, and apoptosis. Here, we present three affected individuals from a consanguineous family of Pakistani origin with variable seizures and intellectual disability. Both females display primary ovarian insufficiency (POI), while the male shows abnormal sex hormone levels. We performed whole exome sequencing and identified a recessive missense variant c.694C > T, p.Arg232Cys in TFAM that segregates with disease. TFAM (mitochondrial transcription factor A) is a component of the mitochondrial replisome machinery that maintains mtDNA transcription and replication. In primary dermal fibroblasts, we show depletion of mtDNA and significantly altered mitochondrial function and morphology. Moreover, we observed reduced nucleoid numbers with significant changes in nucleoid size or shape in fibroblasts from an affected individual compared to controls. We also investigated the effect of tfam impairment in zebrafish; homozygous tfam mutants carrying an in-frame c.141_149 deletion recapitulate the mtDNA depletion and ovarian dysgenesis phenotypes observed in affected humans. Together, our genetic and functional data confirm that TFAM plays a pivotal role in gonad development and expands the repertoire of mitochondrial disease phenotypes.
    DOI:  https://doi.org/10.1007/s00439-021-02380-2
  13. Front Cell Dev Biol. 2021 ;9 737304
    Nicotinamide Riboside and Metformin Ameliorate Mitophagy Defect in Induced Pluripotent Stem Cell-Derived Astrocytes With POLG Mutations.
    Anbin Chen, Cecilie Katrin Kristiansen, Yu Hong, Atefeh Kianian, Evandro Fei Fang, Gareth John Sullivan, Jian Wang, Xingang Li, Laurence A Bindoff, Kristina Xiao Liang.
      Mitophagy specifically recognizes and removes damaged or superfluous mitochondria to maintain mitochondrial homeostasis and proper neuronal function. Defective mitophagy and the resulting accumulation of damaged mitochondria occur in several neurodegenerative diseases. Previously, we showed mitochondrial dysfunction in astrocytes with POLG mutations, and here, we examined how POLG mutations affect mitophagy in astrocytes and how this can be ameliorated pharmacologically. Using induced pluripotent stem cell (iPSC)-derived astrocytes carrying POLG mutations, we found downregulation of mitophagy/autophagy-related genes using RNA sequencing-based KEGG metabolic pathway analysis. We confirmed a deficit in mitochondrial autophagosome formation under exogenous stress conditions and downregulation of the mitophagy receptor p62, reduced lipidation of LC3B-II, and decreased expression of lysosome protein lysosomal-associated membrane protein 2A (LAMP2A). These changes were regulated by the PINK1/Parkin pathway and AKT/mTOR/AMPK/ULK1 signaling pathways. Importantly, we found that double treatment with nicotinamide riboside (NR) and metformin rescued mitophagy defects and mitochondrial dysfunction in POLG-mutant astrocytes. Our findings reveal that impaired mitophagy is involved in the observed mitochondrial dysfunction caused by POLG mutations in astrocytes, potentially contributing to the phenotype in POLG-related diseases. This study also demonstrates the therapeutic potential of NR and metformin in these incurable mitochondrial diseases.
    Keywords:  IPSC (induced pluripotent stem cells); POLG; astrocytes; metformin; mitochondria; mitophagy; nicotinamide riboside (NR)
    DOI:  https://doi.org/10.3389/fcell.2021.737304
  14. Trends Cell Biol. 2021 Oct 08. pii: S0962-8924(21)00183-5. [Epub ahead of print]
    Hierarchical folding of the catalytic core during mitochondrial ribosome biogenesis.
    Elena Lavdovskaia, Hauke S Hillen, Ricarda Richter-Dennerlein.
      Final maturation steps during ribosome biogenesis require the assistance of assembly and quality control factors to ensure the folding of rRNA and proteins into a functional translation machinery. Here we integrate several recent structural snapshots of native large ribosomal subunit intermediates into the complex pathway of mitochondrial ribosome assembly.
    DOI:  https://doi.org/10.1016/j.tcb.2021.09.004
  15. Biosystems. 2021 Oct 07. pii: S0303-2647(21)00201-X. [Epub ahead of print]210 104559
    Reversible and irreversible mitochondrial swelling: Effects of variable mitochondrial activity.
    Igor Khmelinskii, Vladimir Makarov.
      An extended biophysical model was obtained by upgrading the previously reported one (Khmelinskii and Makarov, 2021). The upgraded model accommodates variations of solute transport rates through the inner mitochondrial membrane (IMM) within the mitochondrial population, described by a Gaussian distribution. However, the model may be used for any functional form of the distribution. The dynamics of system parameters as predicted by the current model differed from that predicted by the previous model in the same initial conditions (Khmelinskii and Makarov, 2021). The amount of change varied from one parameter to the other, remaining in the 1-38% range. The upgraded model fitted the available experimental data with a better accuracy (R = 0.993) compared to the previous model (R = 0.978) using the same experimental data (Khmelinskii and Makarov, 2021). The fitting procedure also estimated the Gaussian distribution parameters. The new model requires much larger computational resources, but given its higher accuracy, it may be used for better analysis of experimental data and for better prediction of MS dynamics in different initial conditions. Note that activities of individual mitochondria in mitochondrial populations should vary within biological tissues. Thus, the currently upgraded model is a better tool for biological and bio-medical applications. We believe that this model is much better adapted to the analysis of MS dynamics in vivo.
    Keywords:  Biophysical model; Computation analysis; Irreversible swelling; Mitochondrion; Reversible swelling; Swelling
    DOI:  https://doi.org/10.1016/j.biosystems.2021.104559
  16. Heart Lung Circ. 2021 Oct 06. pii: S1443-9506(21)01203-8. [Epub ahead of print]
    Characterisation of Plasma Mitochondrial DNA, MMP-9 and Neutrophil Elastase in Patients Undergoing Coronary Artery Bypass Grafting: Effects of Tranexamic Acid and Postoperative Pneumonia.
    Nicola Sandler, Heidi Ho, Dominik F Draxler, Christopher R Bain, Julian A Smith, Carl J Hauser, Russell L Gruen, Paul S Myles, Robert L Medcalf.
      BACKGROUND: Postoperative pneumonia is a major cause of morbidity and mortality following cardiac surgery. The inflammatory response to cardiac surgery has been widely studied, but specific mechanisms for postoperative pneumonia have not been determined. Tranexamic acid is renowned for its effect on bleeding but can also modulate inflammatory processes. Cardiac surgery is known to release mitochondrial DAMPs (mtDAMPs) and is linked to postoperative inflammation and atrial fibrillation. We speculated that mtDAMPs might be related to postoperative pneumonia and that this might be modulated by tranexamic acid.METHODS: Forty-one (41) patients from the Aspirin and Tranexamic Acid for Coronary Artery Surgery (ATACAS) trial were studied. Levels of mitochondrial DNA, matrix metallopeptidase 9 (MMP-9) and neutrophil elastase (NE) were determined in plasma preoperatively, at 24 and 72 hours post-surgery and correlated with clinical outcome.
    RESULTS: mtDNA was significantly elevated postoperatively in the placebo and tranexamic acid (TXA) groups. Neutrophil elastase increased immediately postoperatively and at 24 hours. MMP-9 was elevated in the placebo group early postoperatively and in the TXA group at the immediate postoperative time point and after 24 hours. Six (6) of the 41 (14.6%) patients subsequently developed pneumonia. mtDNA levels were significantly increased at the early postoperative period and the 24-hour time point in patients with pneumonia.
    CONCLUSIONS: Cardiac surgery releases mtDNA, increases MMP-9 and NE and this was not influenced by TXA. Inflammation postoperatively might be linked to pneumonia since mtDNA was further elevated in these patients. Due to the low number of individuals developing pneumonia, further studies are warranted to clearly identify whether TXA impacts on the inflammatory response in postoperative pneumonia.
    Keywords:  Mitochondrial DAMPS; Postoperative pneumonia; Tranexamic acid; mtDNA
    DOI:  https://doi.org/10.1016/j.hlc.2021.08.008
  17. Inflamm Res. 2021 Oct 15.
    Emerging perspectives on mitochondrial dysfunctioning and inflammation in epileptogenesis.
    Shareen Singh, Thakur Gurjeet Singh.
      INTRODUCTION: Mitochondrial dysfunction is a common denominator of neuroinflammation recognized by neuronal oxidative stress-mediated apoptosis that is well recognized by common intracellular molecular pathway-interlinked neuroinflammation and mitochondrial oxidative stress, a feature of epileptogenesis. In addition, the neuronal damage in the epileptic brain corroborated the concept of brain injury-mediated neuroinflammation, further providing an interlink between inflammation, mitochondrial dysfunction, and oxidative stress in epilepsy.MATERIALS AND METHODS: A systematic literature review of Bentham, Scopus, PubMed, Medline, and EMBASE (Elsevier) databases was carried out to provide evidence of preclinical and clinically used drugs targeting such nuclear, cytosolic, and mitochondrial proteins suggesting that the correlation of mechanisms linked to neuroinflammation has been elucidated in the current review. Despite that, the evidence of elevated levels of inflammatory mediators and pro-apoptotic protein levels can provide the correlation of inflammatory responses often concerned with hyperexcitability attributing to the fact that mitochondrial redox mechanisms and higher susceptibilities to neuroinflammation result from repetitive recurring epileptic seizures. Therefore, providing an understanding of seizure-induced pathological changes read by activating neuroinflammatory cascades like NF-kB, RIPK, MAPK, ERK, JNK, and JAK-STAT signaling further related to mitochondrial damage promoting hyperexcitability.
    CONCLUSION: The current review highlights the further opportunity for establishing therapeutic interventions underlying the apparent correlation of neuroinflammation mediated mitochondrial oxidative stress might contribute to common intracellular mechanisms underlying a future prospective of drug treatment targeting mitochondrial dysfunction linked to the neuroinflammation in epilepsy.
    Keywords:  Epilepsy; Mitochondrial dysfunction; Neurodegeneration; Neuroinflammation; Oxidative stress
    DOI:  https://doi.org/10.1007/s00011-021-01511-9
  18. Acta Biomater. 2021 Oct 12. pii: S1742-7061(21)00683-8. [Epub ahead of print]
    Mitochondrial Ca2+-overloading by oxygen/glutathione depletion-boosted photodynamic therapy based on a CaCO3 nanoplatform for tumor synergistic therapy.
    Jiawei Zhu, Aihong Jiao, Qinzhe Li, Xinyi Lv, Xiaorui Wang, Xuejiao Song, Buhong Li, Yewei Zhang, Xiaochen Dong.
      The Ca2+ buffering capacity of mitochondria maintains the balance of cell physiological activities. The exogenous reactive oxygen species (ROS) can be used to break the balance, resulting in mitochondrial dysfunction and irreversible cell apoptosis. Herein, the CaCO3-based tumor microenvironment (TME) responsive nanoplatform (CaNPCAT+BSO@Ce6-PEG) was designed for oxygen/GSH depletion-boosted photodynamic therapy (PDT) and mitochondrial Ca2+-overloading synergistic therapy. In acidic TME, CaCO3 decomposed and released the cargos (catalase (CAT), buthionine sulfoximine (BSO), chlorin e6 (Ce6), and Ca2+). The tumor hypoxia and reductive microenvironment could be significantly reversed by CAT and BSO, which greatly enhanced the PDT efficacy. The generated 1O2 during PDT process not only directly killed cancer cells but also destroyed the Ca2+ buffering capacity, leading to the mitochondrial Ca2+-overloading. The increased Ca2+ concentration promoted the process of oxidative phosphorylation and inhibited the production of adenosine triphosphate (ATP), resulting in the acceleration of cell death. Under the joint action of enhanced PDT and mitochondrial Ca2+-overloading, the CaNPCAT+BSO@Ce6-PEG NPs showed remarkable synergistic effects in tumor inhibition without any side effects. STATEMENT OF SIGNIFICANCE: In the manuscript, a CaCO3-based nano-platform for tumor microenvironment response was designed. With the decomposition of CaNPCAT+BSO@Ce6-PEG NPs in the acidic tumor microenvironment, the released catalase (CAT) and buthionine sulfoximine (BSO) could relieve the tumor hypoxia and inhibit GSH production. Under 660 nm laser irradiation, the photodynamic effect was enhanced and caused apoptosis. Meanwhile, the Ca2+ buffering capacity was destroyed which led to the mitochondrial Ca2+-overloading. The synergistic effect of enhanced PDT and mitochondrial Ca2+-overloading made the CaNPCAT+BSO@Ce6-PEG NPs present remarkable antitumor performance.
    Keywords:  Ca(2+)-buffering capacity; Ca(2+)-overloading; Mitochondrial dysfunction; Oxygen/GSH depletion; Photodynamic therapy
    DOI:  https://doi.org/10.1016/j.actbio.2021.10.016
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