bims-midmar Biomed News
on Mitochondrial DNA maintenance and replication
Issue of 2022‒02‒13
eleven papers selected by
Flavia Söllner
Ludwig-Maximilians University
  1. The fate of damaged mitochondrial DNA in the cell.
  2. In vivo mitochondrial base editing via adeno-associated viral delivery to mouse post-mitotic tissue.
  3. Unwinding the mutational signatures of a DNA topoisomerase enzyme.
  4. New insights into mitochondrial-nuclear interactions revealed through analysis of small RNAs.
  5. Next-generation sequencing of the whole mitochondrial genome identifies functionally deleterious mutations in patients with multiple sclerosis.
  6. Retinal Degeneration Associated With the G1606A Mitochondrial Mutation.
  7. Identification of Mitochondrial DNA Variants Associated With Risk of Neuroblastoma.
  8. Mitochondrial DNA and Epigenetics: Investigating Interactions with the One-Carbon Metabolism in Obesity.
  9. Role of mitochondria DNA A10398G polymorphism on development of Parkinson's disease: A PRISMA-compliant meta-analysis.
  10. Flaviviridae and mitochondria: Everything you always wanted to know about their relationship but were afraid to ask.
  11. Flow Cytometry Analysis of Planarian Stem Cells Using DNA and Mitochondrial Dyes.
  1. Biochim Biophys Acta Mol Cell Res. 2022 Feb 04. pii: S0167-4889(22)00024-6. [Epub ahead of print] 119233
    The fate of damaged mitochondrial DNA in the cell.
    Siyang Liao, Li Chen, Zhiyin Song, He He.
      Mitochondrion is a double membrane organelle that is responsible for cellular respiration and production of most of the ATP in eukaryotic cells. Mitochondrial DNA (mtDNA) is the genetic material carried by mitochondria, which encodes some essential subunits of respiratory complexes independent of nuclear DNA. Normally, mtDNA binds to certain proteins to form a nucleoid that is stable in mitochondria. Nevertheless, a variety of physiological or pathological stresses can cause mtDNA damage, and the accumulation of damaged mtDNA in mitochondria leads to mitochondrial dysfunction, which triggers the occurrence of mitochondrial diseases in vivo. In response to mtDNA damage, cell initiates multiple pathways including mtDNA repair, degradation, clearance and release, to recover mtDNA, and maintain mitochondrial quality and cell homeostasis. In this review, we provide our current understanding of the fate of damaged mtDNA, focus on the pathways and mechanisms of removing damaged mtDNA in the cell.
    Keywords:  Mitochondria DNA (mtDNA); Mitocytosis; Mitophagy; mtDNA release
    DOI:  https://doi.org/10.1016/j.bbamcr.2022.119233
  2. Nat Commun. 2022 Feb 08. 13(1): 750
    In vivo mitochondrial base editing via adeno-associated viral delivery to mouse post-mitotic tissue.
    Pedro Silva-Pinheiro, Pavel A Nash, Lindsey Van Haute, Christian D Mutti, Keira Turner, Michal Minczuk.
      Mitochondria host key metabolic processes vital for cellular energy provision and are central to cell fate decisions. They are subjected to unique genetic control by both nuclear DNA and their own multi-copy genome - mitochondrial DNA (mtDNA). Mutations in mtDNA often lead to clinically heterogeneous, maternally inherited diseases that display different organ-specific presentation at any stage of life. For a long time, genetic manipulation of mammalian mtDNA has posed a major challenge, impeding our ability to understand the basic mitochondrial biology and mechanisms underpinning mitochondrial disease. However, an important new tool for mtDNA mutagenesis has emerged recently, namely double-stranded DNA deaminase (DddA)-derived cytosine base editor (DdCBE). Here, we test this emerging tool for in vivo use, by delivering DdCBEs into mouse heart using adeno-associated virus (AAV) vectors and show that it can install desired mtDNA edits in adult and neonatal mice. This work provides proof-of-concept for use of DdCBEs to mutagenize mtDNA in vivo in post-mitotic tissues and provides crucial insights into potential translation to human somatic gene correction therapies to treat primary mitochondrial disease phenotypes.
    DOI:  https://doi.org/10.1038/s41467-022-28358-w
  3. Nature. 2022 Feb 09.
    Unwinding the mutational signatures of a DNA topoisomerase enzyme.
    Ammal Abbasi, Ludmil B Alexandrov.
      
    Keywords:  Cancer; Molecular biology
    DOI:  https://doi.org/10.1038/d41586-022-00301-5
  4. Genome Biol Evol. 2022 Feb 10. pii: evac023. [Epub ahead of print]
    New insights into mitochondrial-nuclear interactions revealed through analysis of small RNAs.
    Andrea Pozzi, Damian K Dowling.
      Mitochondrial sequence variants affect phenotypic function, often through interaction with the nuclear genome. These "mitonuclear" interactions have been linked both to evolutionary processes and human health. The study of these interactions has focused on mechanisms regulating communication between mitochondrial and nuclear proteins; the role of mitochondrial (mt) RNAs has received little attention. Here, we show that small mt-RNAs bind to the nuclear protein Argonaute 2, and that nuclear miRNAs bind to mt-mRNAs. We identify one small mt-RNA that binds to Argonaute 2 in human tissues whose expression and sequence remain unchanged across vertebrates. While analyses of CLEAR-CLIP sequencing datasets of human and mouse did not reveal consistent interactions between small mt-RNAs and nuclear mRNAs, we found that MT-ND4 and MT-ATP6 mRNAs are bound by different nuclear miRNAs in humans and mice. Our work homes in on previously unknown interactions between nuclear and small mt-RNAs, which may play key roles in intergenomic communication.
    Keywords:  AGO2; Mitonuclear communication; mitochondria; mtDNA; small RNAs
    DOI:  https://doi.org/10.1093/gbe/evac023
  5. PLoS One. 2022 ;17(2): e0263606
    Next-generation sequencing of the whole mitochondrial genome identifies functionally deleterious mutations in patients with multiple sclerosis.
    Ghada Al-Kafaji, Halla F Bakheit, Faisal AlAli, Mina Fattah, Saad Alhajeri, Maram A Alharbi, Abdulqader Daif, Manahel Mahmood Alsabbagh, Materah Salem Alwehaidah, Moiz Bakhiet.
      Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system with genetics and environmental determinants. Studies focused on the neurogenetics of MS showed that mitochondrial DNA (mtDNA) mutations that can ultimately lead to mitochondrial dysfunction, alter brain energy metabolism and cause neurodegeneration. We analyzed the whole mitochondrial genome using next-generation sequencing (NGS) from 47 Saudi individuals, 23 patients with relapsing-remitting MS and 24 healthy controls to identify mtDNA disease-related mutations/variants. A large number of variants were detected in the D-loop and coding genes of mtDNA. While distinct unique variants were only present in patients or only occur in controls, a number of common variants were shared among the two groups. The prevalence of some common variants differed significantly between patients and controls, thus could be implicated in susceptibility to MS. Of the unique variants only present in the patients, 34 were missense mutations, located in different mtDNA-encoded genes. Seven of these mutations were not previously reported in MS, and predicted to be deleterious with considerable impacts on the functions and structures of encoded-proteins and may play a role in the pathogenesis of MS. These include two heteroplasmic mutations namely 10237T>C in MT-ND3 gene and 15884G>C in MT-CYB gene; and three homoplasmic mutations namely 9288A>G in MT-CO3 gene, 14484T>C in MT-ND6 gene, 15431G>A in MT-CYB gene, 8490T>C in MT-ATP8 gene and 5437C>T in MT-ND2 gene. Notably some patients harboured multiple mutations while other patients carried the same mutations. This study is the first to sequence the entire mitochondrial genome in MS patients in an Arab population. Our results expanded the mutational spectrum of mtDNA variants in MS and highlighted the efficiency of NGS in population-specific mtDNA variant discovery. Further investigations in a larger cohort are warranted to confirm the role of mtDNA MS.
    DOI:  https://doi.org/10.1371/journal.pone.0263606
  6. Ophthalmic Surg Lasers Imaging Retina. 2022 Feb;53(2): 116-119
    Retinal Degeneration Associated With the G1606A Mitochondrial Mutation.
    Hana A Mansour, Joseph A Chacko, Riley N Sanders, Gerald B Schaefer, Sami H Uwaydat.
      The guanine-to-adenine substitution at nucleotide 1606 (G1606A) mutation in the mitochondrial DNA transfer RNA-valine gene has been reported to cause sensorineural deafness, ataxia, myoclonus, seizures, and mental retardation. This study hereby presents a single case report of a new retinal phenotype associated with this mutation: a middle-aged woman with retinal pigment epithelium stippling, atrophy, and peripapillary (retinal pigment epithelium) dropout on fundus examination. The patient was administered an empiric trial of a mitochondrial cocktail with close monitoring of her systemic symptoms. This study identified a novel G1606A mutation to cause early-onset macular pathology resembling that previously described in the A3243G mutation. [Ophthalmic Surg Lasers Imaging Retina. 2022;53:116-119.].
    DOI:  https://doi.org/10.3928/23258160-20220121-04
  7. J Natl Cancer Inst. 2022 Feb 02. pii: djac012. [Epub ahead of print]
    Identification of Mitochondrial DNA Variants Associated With Risk of Neuroblastoma.
    Xiao Chang, Yichuan Liu, Joseph Glessner, Cuiping Hou, Huiqi Qu, Kenny Nguyen, Patrick Sleiman, Lobin Lee, Sharon J Diskin, John M Maris, Hakon Hakonarson.
      Neuroblastoma is a childhood cancer that originates in the developing sympathetic nervous system. We previously reported a crucial role of mitochondrial DNA (mtDNA) haplogroups in the pathology of neuroblastoma. To pinpoint mtDNA variants associated with neuroblastoma risk, we applied a mitochondrial genome imputation pipeline to the SNP array data of two pediatric cohorts containing a total of 2,404 neuroblastoma cases and 9,310 cancer-free controls. All statistical tests were 2-sided. The single nucleotide variant, rs2853493, was statistically significantly associated with neuroblastoma risk in the discovery cohort (odds ratio = 0.62, 95% CI = 0.53-0.72, P < .001) and further confirmed in the replication cohort (odds ratio = 0.75, 95% CI = 0.62-0.90, P = .002). Further, eQTL analysis indicated genotypes of rs2853493 were associated with expression levels of MT-CYB gene expression in neuroblastoma cells suggesting rs2853493 may confer risk to neuroblastoma via regulating the expression level of its nearby genes.
    DOI:  https://doi.org/10.1093/jnci/djac012
  8. Oxid Med Cell Longev. 2022 ;2022 9171684
    Mitochondrial DNA and Epigenetics: Investigating Interactions with the One-Carbon Metabolism in Obesity.
    Laura Bordoni, Irene Petracci, Monika Mlodzik-Czyzewska, Anna M Malinowska, Artur Szwengiel, Marcin Sadowski, Rosita Gabbianelli, Agata Chmurzynska.
      Mitochondrial DNA copy number (mtDNAcn) has been proposed for use as a surrogate biomarker of mitochondrial health, and evidence suggests that mtDNA might be methylated. Intermediates of the one-carbon cycle (1CC), which is duplicated in the cytoplasm and mitochondria, have a major role in modulating the impact of diet on the epigenome. Moreover, epigenetic pathways and the redox system are linked by the metabolism of glutathione (GSH). In a cohort of 101 normal-weight and 97 overweight/obese subjects, we evaluated mtDNAcn and methylation levels in both mitochondrial and nuclear areas to test the association of these marks with body weight, metabolic profile, and availability of 1CC intermediates associated with diet. Body composition was associated with 1CC intermediate availability. Reduced levels of GSH were measured in the overweight/obese group (p = 1.3∗10-5). A high BMI was associated with lower LINE-1 (p = 0.004) and nominally lower methylenetetrahydrofolate reductase (MTHFR) gene methylation (p = 0.047). mtDNAcn was lower in overweight/obese subjects (p = 0.004) and independently correlated with MTHFR methylation levels (p = 0.005) but not to LINE-1 methylation levels (p = 0.086). DNA methylation has been detected in the light strand but not in the heavy strand of the mtDNA. Although mtDNA methylation in the light strand did not differ between overweight/obese and normal-weight subjects, it was nominally correlated with homocysteine levels (p = 0.035) and MTHFR methylation (p = 0.033). This evidence suggests that increased body weight might perturb mitochondrial-nuclear homeostasis affecting the availability of nutrients acting as intermediates of the one-carbon cycle.
    DOI:  https://doi.org/10.1155/2022/9171684
  9. J Clin Lab Anal. 2022 Feb 11. e24274
    Role of mitochondria DNA A10398G polymorphism on development of Parkinson's disease: A PRISMA-compliant meta-analysis.
    I-Shiang Tzeng.
      BACKGROUND: Parkinson's disease (PD) is characterized by memory loss and multiple cognitive disorders caused primarily by neurodegeneration. However, the preventative effects of the mitochondrial A10398G DNA polymorphism remain controversial. This meta-analysis comprehensively assessed evidence on the influence of the mitochondrial DNA A10398G variant on PD development.METHODS: The PubMed, EMBASE, EBSCO, Springer Link, and Web of Science databases were searched from inception to May 31, 2020. We used a pooled model with random effects to explore the effect of A10398G on the development of PD. Stata MP version 14.0 was used to calculate the odds ratios and 95% confidence intervals (CIs) from the eligible studies to assess the impact of mitochondrial DNA A10398G on PD development.
    RESULTS: The overall survey of the populations showed no significant association between mitochondrial DNA A10398G polymorphism (G allele compared to A allele) and PD (odds ratio = 0.85, 95% CI = 0.70-1.04, p = 0.111); however, a significant association between the mutation and PD was observed in the Caucasian population (odds ratio = 0.71, 95% CI = 0.58-0.87, p = 0.001). A neutral effect was observed in the Asian population (odds ratio = 1.10, 95% CI = 0.94-1.28, p = 0.242).
    CONCLUSIONS: The results of this meta-analysis showed the potential protective effect of the mitochondrial DNA A10398G polymorphism on the risk of developing PD in the Caucasian population. Studies with better designs and larger samples with intensive work are required to validate these results.
    Keywords:  Parkinson's disease; allele; mitochondrial DNA; neurogenesis
    DOI:  https://doi.org/10.1002/jcla.24274
  10. Virologie (Montrouge). 2022 Feb 10.
    Flaviviridae and mitochondria: Everything you always wanted to know about their relationship but were afraid to ask.
    Wesley Freppel, Marie Roy, Laurent Chatel-Chaix.
      Infections with Flaviviridae constitute a major public health concern, especially considering the limited availability of prophylactic and therapeutic treatments. Most notably, the recent emergence of Zika virus in the Americas was associated with the dramatic increase of severe symptoms such as congenital microcephaly, while hepatitis C virus causes the death of approximately 300,000 individuals annually. Flaviviridae have evolved to hijack cellular organelles and to favor their replication, often via divergent molecular mechanisms. In addition to the remodeling of the endoplasmic reticulum, which is required for the replication of the viral genome and the assembly of the neosynthesized virions, Flaviviridae induce drastic morphological alterations of the mitochondria. This is associated with the viral co-opting of several key mitochondrial functions in apoptosis, innate immunity and metabolism. This review recapitulates the current knowledge about the morphological and functional relationship between Flaviviridae and mitochondria and explains how this contributes to the establishment of a cytoplasmic environment which is favorable to viral replication.
    Keywords:  apoptosis; flavivirus; hepatitis C virus; innate immunity; mitochondria; mitochondria morphodynamics
    DOI:  https://doi.org/10.1684/vir.2022.0926
  11. Bio Protoc. 2022 Jan 20. 12(2): e4299
    Flow Cytometry Analysis of Planarian Stem Cells Using DNA and Mitochondrial Dyes.
    Mohamed Mohamed Haroon, Praveen Kumar Vemula, Dasaradhi Palakodeti.
      Planarians are free-living flatworms that emerged as a crucial model system to understand regeneration and stem cell biology. The ability to purify neoblasts, the adult stem cell population of planaria, through fluorescence-activated cell sorting (FACS) has tremendously increased our understanding of pluripotency, specialization, and heterogeneity. To date, the FACS-based purification methods for neoblasts relied on nuclear dyes that discriminate proliferating cells (>2N), as neoblasts are the only dividing somatic cells. However, this method does not distinguish the functional states within the neoblast population. Our work has shown that among the neoblasts, the pluripotent stem cells (PSCs) are associated with low mitochondrial content and this property could be leveraged for purification of the PSC-enriched population. Using the mitochondrial dye MitoTracker Green (MTG) and the nuclear dye SiR-DNA, we have described a method for isolation of PSCs that are viable and compatible with downstream experiments, such as transplantation and cell culture. In this protocol, we provide a detailed description for sample preparation and FACS gating for neoblast isolation in planaria.
    Keywords:  FACS; Mitochondria; Planaria; Pluripotency; Regeneration; Stem cells
    DOI:  https://doi.org/10.21769/BioProtoc.4299
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