bims-midmar Biomed News
on Mitochondrial DNA maintenance and replication
Issue of 2022‒02‒06
eleven papers selected by
Flavia Söllner
Ludwig-Maximilians University
  1. Mitochondrial DNA Homeostasis Impairment and Dopaminergic Dysfunction: A Trembling Balance.
  2. Understanding the nomenclature of mitochondrial DNA mutations through examples of two specific disease entities: Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes and Leber hereditary optic neuropathy.
  3. Mitochondrial- and nuclear genome-controlled bioenergetic gene expression in Alzheimer's disease.
  4. Complexome Profiling-Exploring Mitochondrial Protein Complexes in Health and Disease.
  5. Mitochondrial DNA copy number as a prognostic marker is age-dependent in adult glioblastoma.
  6. Mitochondrial DNA content: a new potential biomarker for Sudden Infant Death Syndrome.
  7. Yme2, a putative RNA recognition motif and AAA+ domain containing protein, genetically interacts with the mitochondrial protein export machinery.
  8. mtDNA mutations help support cancer cells.
  9. Mitochondrial hijacking: a potential mechanism for SARS-CoV-2 to impair female fertility.
  10. Mitochondrial gene expression analysis reveals aberrant transcription of cox3 in Gossypium barbadense CMS line H276A.
  11. Mitochondria, a Missing Link in COVID-19 Heart Failure and Arrest?
  1. Ageing Res Rev. 2022 Jan 31. pii: S1568-1637(22)00020-4. [Epub ahead of print] 101578
    Mitochondrial DNA Homeostasis Impairment and Dopaminergic Dysfunction: A Trembling Balance.
    Arianna Manini, Elena Abati, Giacomo Pietro Comi, Stefania Corti, Dario Ronchi.
      Maintenance of mitochondrial DNA (mtDNA) homeostasis includes a variety of processes, such as mtDNA replication, repair, and nucleotides synthesis, aimed at preserving the structural and functional integrity of mtDNA molecules. Mutations in several nuclear genes (i.e., POLG, POLG2, TWNK, OPA1, DGUOK, MPV17, TYMP) impair mtDNA maintenance, leading to clinical syndromes characterized by mtDNA depletion and/or deletions in affected tissues. In the past decades, studies have demonstrated a progressive accumulation of multiple mtDNA deletions in dopaminergic neurons of the substantia nigra in elderly population and, to a greater extent, in Parkinson's disease patients. Moreover, parkinsonism has been frequently described as a prominent clinical feature in mtDNA instability syndromes. Among Parkinson's disease-related genes with a significant role in mitochondrial biology, PARK2 and LRRK2 specifically take part in mtDNA maintenance. Moreover, a variety of murine models (i.e., "Mutator", "MitoPark", "PD-mitoPstI", "Deletor", "Twinkle-dup" and "TwinkPark") provided in vivo evidence that mtDNA stability is required to preserve nigrostriatal integrity. Here, we review and discuss the clinical, genetic, and pathological background underlining the link between impaired mtDNA homeostasis and dopaminergic degeneration.
    Keywords:  POLG1, Twinkle; Parkinsonism; Parkinson’s disease; mitochondrion; mtDNA homeostasis
    DOI:  https://doi.org/10.1016/j.arr.2022.101578
  2. J Am Assoc Nurse Pract. 2022 Feb 01. 34(2): 217-219
    Understanding the nomenclature of mitochondrial DNA mutations through examples of two specific disease entities: Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes and Leber hereditary optic neuropathy.
    Beth Heuer, Diane C Seibert.
      ABSTRACT: Mitochondrial diseases are genetic disorders that can arise either from maternally inherited mitochondrial DNA (mtDNA) or from mutations in nuclear DNA. This article is the second in a series of papers reviewing mitochondrial genetics and several of the disorders associated with mitochondrial gene variants. With a prevalence of 1:∼4,300 persons, mitochondrial disorders are diagnostic entities with which nurse practitioners should be familiar. In describing genetic mutations, numbering nucleotides (nuclear or mtDNA) is critical for communicating exactly where a variation has occurred in a stretch of nucleotides. This article discusses the nomenclature associated with mtDNA mutations, using the examples of mutations causing mitochondrial encephalopathy with lactic acidosis and stroke-like episodes and Leber hereditary optic neuropathy. Pathophysiology, symptoms, and treatment options for these disease entities are discussed.
    DOI:  https://doi.org/10.1097/JXX.0000000000000693
  3. Alzheimers Dement. 2021 Dec;17 Suppl 3 e054460
    Mitochondrial- and nuclear genome-controlled bioenergetic gene expression in Alzheimer's disease.
    Yuan Shang, Fei Yin, Roberta Diaz Brinton.
      BACKGROUND: Mitochondrial dysfunction is a hallmark of brain aging and particularly accentuated in neurodegenerative diseases including Alzheimer's disease (AD), yet the regulation of mitochondrial DNA (mtDNA) versus nuclear DNA (nDNA)-encoded genes in the aging- and AD brains is largely unknown.METHOD: Transcriptome datasets (ROSMAP, Mayo, and MSBB) and proteome dataset (ROSMAP) from cognitively normal and AD brains were analyzed. Linear regression models were applied to evaluate the association between mtDNA-encoded and nDNA-encoded genes at transcript and protein levels. Further, pathway analysis was performed to identify biological processes correlated with mtDNA-encoded gene expression.
    RESULT: At transcript level, mtDNA encoded genes were uniformly regulated (average R2 ranging from 0.43 to 0.92) across all datasets analyzed. While mtDNA encoded and nDNA encoded oxidative phosphorylation (OXPHOS) genes were positively correlated at protein level, they were differentially regulated at transcript level. Compared to control brains, both genesets were downregulated in AD brains at protein level whereas at the transcript level, mtDNA transcript number was higher vs nDNA transcript number was lower. In addition, transcriptional correlations between nDNA OXPHOS genes and mtDNA genes were reduced in AD brains. In both normal and AD brains, mtDNA transcripts were consistently correlated with Alzheimer's related pathways, including a positive correlation with notch signaling module and negative correlations with synapse, mitochondrial, translation, and ubiquitin mediated protein clearance modules. Across brain cell types, neuronal cell markers were negatively correlated with mtDNA transcripts whereas markers for oligodendrocyte, astrocyte and endothelial cells exhibited positive correlations.
    CONCLUSION: Outcomes of these analyses suggest an underappreciated correlation between mitochondrial gene expression with the development of AD, in particular the coordinated transcriptional regulation across both the mitochondrial- and nuclear genomes. While mitochondria are a promising therapeutic target for Alzheimer's disease, the findings reported herein indicate that restoring optimal mitochondrial function to prevent or treat Alzheimer's remains a complex challenge. This work was supported by National Institute on Aging grants P01-AG026572, R01 AG057931, and R01 AG059093 to RDB.
    DOI:  https://doi.org/10.1002/alz.054460
  4. Front Cell Dev Biol. 2021 ;9 796128
    Complexome Profiling-Exploring Mitochondrial Protein Complexes in Health and Disease.
    Alfredo Cabrera-Orefice, Alisa Potter, Felix Evers, Johannes F Hevler, Sergio Guerrero-Castillo.
      Complexome profiling (CP) is a state-of-the-art approach that combines separation of native proteins by electrophoresis, size exclusion chromatography or density gradient centrifugation with tandem mass spectrometry identification and quantification. Resulting data are computationally clustered to visualize the inventory, abundance and arrangement of multiprotein complexes in a biological sample. Since its formal introduction a decade ago, this method has been mostly applied to explore not only the composition and abundance of mitochondrial oxidative phosphorylation (OXPHOS) complexes in several species but also to identify novel protein interactors involved in their assembly, maintenance and functions. Besides, complexome profiling has been utilized to study the dynamics of OXPHOS complexes, as well as the impact of an increasing number of mutations leading to mitochondrial disorders or rearrangements of the whole mitochondrial complexome. Here, we summarize the major findings obtained by this approach; emphasize its advantages and current limitations; discuss multiple examples on how this tool could be applied to further investigate pathophysiological mechanisms and comment on the latest advances and opportunity areas to keep developing this methodology.
    Keywords:  complexome profiling; disease; mass spectrometry; mitochondria; oxidative phosphorylation; protein complex; protein-protein interaction (PPI); proteomics
    DOI:  https://doi.org/10.3389/fcell.2021.796128
  5. Neurooncol Adv. 2022 Jan-Dec;4(1):4(1): vdab191
    Mitochondrial DNA copy number as a prognostic marker is age-dependent in adult glioblastoma.
    Baptiste Sourty, Laure-Marie Dardaud, Céline Bris, Valérie Desquiret-Dumas, Blandine Boisselier, Laëtitia Basset, Dominique Figarella-Branger, Alain Morel, Marc Sanson, Vincent Procaccio, Audrey Rousseau.
      Background: Glioblastoma (GBM) is the most common and aggressive form of glioma. GBM frequently displays chromosome (chr) 7 gain, chr 10 loss and/or EGFR amplification (chr7+/chr10-/EGFRamp). Overall survival (OS) is 15 months after treatment. In young adults, IDH1/2 mutations are associated with longer survival. In children, histone H3 mutations portend a dismal prognosis. Novel reliable prognostic markers are needed in GBM. We assessed the prognostic value of mitochondrial DNA (mtDNA) copy number in adult GBM.Methods: mtDNA copy number was assessed using real-time quantitative PCR in 232 primary GBM. Methylation of POLG and TFAM genes, involved in mtDNA replication, was assessed by bisulfite-pyrosequencing in 44 and 51 cases, respectively.
    Results: Median age at diagnosis was 56.6 years-old and median OS, 13.3 months. 153/232 GBM (66 %) displayed chr7+/chr10-/EGFRamp, 23 (9.9 %) IDH1/2 mutation, 3 (1.3 %) H3 mutation and 53 (22.8 %) no key genetic alterations. GBM were divided into two groups, "Low" (n = 116) and "High" (n = 116), according to the median mtDNA/nuclear DNA ratio (237.7). There was no significant difference in OS between the two groups. By dividing the whole cohort according to the median age at diagnosis, OS was longer in the "High" vs "Low" subgroup (27.3 vs 15 months, P = .0203) in young adult GBM (n = 117) and longer in the "Low" vs "High" subgroup (14.5 vs 10.2 months, P = .0116) in older adult GBM (n = 115). POLG was highly methylated, whereas TFAM remained unmethylated.
    Conclusion: mtDNA copy number may be a novel prognostic biomarker in GBM, its impact depending on age.
    Keywords:  glioblastoma; metabolism; methylation; mitochondrial DNA; prognosis
    DOI:  https://doi.org/10.1093/noajnl/vdab191
  6. Pediatr Res. 2022 Feb 01.
    Mitochondrial DNA content: a new potential biomarker for Sudden Infant Death Syndrome.
    Roberta Danusso, Graziella Alfonsi, Stefano Ferrero, Anna Maria Lavezzi, Debora Lattuada.
      BACKGROUND: Sudden Infant Death Syndrome (SIDS) occurs in apparently healthy infants and is unpredictable and unexplained despite thorough investigations and enormous research efforts. The hypothesis tested in this case-control study concerns mitochondrial involvement in SIDS occurrence.METHODS: Mitochondrial DNA content (MtDNAcn) was measured in 24 SIDS cerebral cortex samples and 18 controls using real-time PCR.
    RESULTS: The median (interquartile range) mtDNAcn in SIDS and controls was 2578 (2224-3838) and 1452 (724-2517) copies per nuclear DNA, respectively (P = 0.0001). MtDNAcn values were higher in SIDS victims born to non-smoking parents (n = 7) 4984 (2832-6908) compared to the controls (n = 5) 2020 (478-2386) (P = 0.006). Increased levels of mtDNAcn have been observed in the SIDS cases with mild defects in nuclei not essential for life compared to those found in SIDS cases with severe alterations of respiratory function (P = 0.034) 3571 (2568-5053) (n = 14) 2356 (1909-3132) (n = 8), respectively.
    CONCLUSIONS: Our study revealed for the first time higher mtDNAcn in the cerebral cortex of the SIDS cases than the controls, indicating metabolic alterations. MtDNAcn plays an important role in compensatory mechanisms against environmental factors affecting human health. Despite the small sample size, mtDNA may prove to be a potential forensic biomarker for autopsied SIDS victims for gaining new insights into the etiology of SIDS.
    IMPACT: Mitochondrial DNA content evaluated in cerebral cortex samples is higher in SIDS victims than controls. These results represent a novel line of investigation for the etiology of SIDS and could have a significant role in the compensatory mechanism due to environmental factors affecting human health. These findings suggest that the mitochondria are involved in SIDS: mtDNA content may represent a biomarker of this syndrome.
    DOI:  https://doi.org/10.1038/s41390-021-01901-z
  7. Biol Chem. 2022 Jan 31.
    Yme2, a putative RNA recognition motif and AAA+ domain containing protein, genetically interacts with the mitochondrial protein export machinery.
    Nupur Sharma, Christof Osman.
      The mitochondrial respiratory chain is composed of nuclear as well as mitochondrial-encoded subunits. A variety of factors mediate co-translational integration of mtDNA-encoded proteins into the inner membrane. In Saccharomyces cerevisiae, Mdm38 and Mba1 are ribosome acceptors that recruit the mitochondrial ribosome to the inner membrane, where the insertase Oxa1, facilitates membrane integration of client proteins. The protein Yme2 has previously been shown to be localized in the inner mitochondrial membrane and has been implicated in mitochondrial protein biogenesis, but its mode of action remains unclear. Here, we show that multiple copies of Yme2 assemble into a high molecular weight complex. Using a combination of bioinformatics and mutational analyses, we find that Yme2 possesses an RNA recognition motif (RRM), which faces the mitochondrial matrix and a AAA+ domain that is located in the intermembrane space. We further show that YME2 genetically interacts with MDM38, MBA1 and OXA1, which links the function of Yme2 to the mitochondrial protein biogenesis machinery.
    Keywords:  MBA1; MDM38; OXA1; RRM; Walker motifs; mitoribosome
    DOI:  https://doi.org/10.1515/hsz-2021-0398
  8. Nat Cancer. 2020 Oct;1(10): 941-942
    mtDNA mutations help support cancer cells.
    Hiran A Prag, Michael P Murphy.
      
    DOI:  https://doi.org/10.1038/s43018-020-00128-x
  9. Med Hypotheses. 2022 Jan 25. 110778
    Mitochondrial hijacking: a potential mechanism for SARS-CoV-2 to impair female fertility.
    Jun Sun, Qiong Liu, Xinling Zhang, Shu Dun, Li Liu.
      As well as causing respiratory lesions, the multi-organ complications caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are also well known. Combined with the epidemiological characteristics of SARS-CoV-2 with high transmission rate and low lethality, the impact of complications caused by its infection on infected individuals seems to be of greater concern. There has been evidence that viral infection is complicated by female reproductive impairment, but the mechanism by which SARS-CoV-2 impairs female fertility is unclear. In addition, RNA-GPS technology has revealed that the SARS-CoV-2 genome resides in mitochondria of the host cells and affects mitochondrial function. Considering the close relationship between mitochondria and female fertility, this paper takes mitochondrial hijacking as an entry point to elucidate the possible mechanisms by which SARS-CoV-2 affects female fertility through the mitochondrial hijacking pathway, which will be important for timely preventive measures and identification of therapeutic targets for infected women with reproductive needs, especially those with asymptomatic infection.
    Keywords:  ACE2; Fertility; Mitochondria; Oocytes; SARS-CoV-2
    DOI:  https://doi.org/10.1016/j.mehy.2022.110778
  10. Dev Genes Evol. 2022 Jan 29.
    Mitochondrial gene expression analysis reveals aberrant transcription of cox3 in Gossypium barbadense CMS line H276A.
    Aziz Khan, Xiangjun Kong, Xiaofang Liao, Jie Zheng, Jingyi You, Min Li, Reem M Hussain, Haneef Raza, Ruiyang Zhou.
      Cotton cytoplasmic male sterility (CMS) has been extensively studied; however, information regarding its molecular mechanisms has not yet been disclosed. Therefore, to explore the molecular mechanism of pollen abortion of cotton CMS line H276A, transcript profiles of 30 mitochondrial protein-encoding genes at tetrad stage were conducted with northern blot and a differential expression gene cox3 was identified. Quantitative reverse-transcribed PCR (qRT-PCR) analysis indicated that the expression level of cox3 in the CMS line H276A was 0.39-fold compared to its maintainer line H276B. In addition, the immunoblot analysis revealed that the amount of COX3 protein was decreased to 59.38% in CMS line H276A. The 5` and 3` terminals of the transcript of cox3 in two materials were determined simultaneously with circularized RNA reverse-transcribed PCR (CR-RT-PCR). The data indicated that seven 5` end of transcript of cox3 in H276A (-451/-464/-465/-467/-471/-472/-508 respect to ATG) were identified which were different from that of H276B (-411/-412). A total of 15 single nucleotide polymorphisms (SNPs) was detected by clone sequencing analysis of upstream of cox3. To our knowledge, we are the first to comprehensively analyze the transcripts of the mitochondrial genome in the cotton CMS line and to identify the 5` and 3` terminals of the transcript of cox3 in cotton. Our data will provide a framework for a better understanding of molecular mechanisms of CMS and mitochondrial gene expression in cotton.
    Keywords:  Circularized RNA reverse-transcribed PCR; Cotton (Gossypium barbadense); Cytoplasmic male sterility; Mitochondrial genes
    DOI:  https://doi.org/10.1007/s00427-022-00685-4
  11. Front Cardiovasc Med. 2021 ;8 830024
    Mitochondria, a Missing Link in COVID-19 Heart Failure and Arrest?
    Ralph Ryback, Alfonso Eirin.
      
    Keywords:  ATP; COVID-19; cardiovascular disease; heart failure; mitochondria
    DOI:  https://doi.org/10.3389/fcvm.2021.830024
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