bims-midmar Biomed News
on Mitochondrial DNA maintenance and replication
Issue of 2022–01–23
thirteen papers selected by
Flavia Söllner, Ludwig-Maximilians University
  1. Mitochondrial DNA copy number and disease.
  2. Molecular Phylogenetics and Mitochondrial Evolution.
  3. Association of mitochondrial DNA copy number with cardiometabolic diseases.
  4. The role of mtDNA haplogroups on metabolic features in narcolepsy type 1.
  5. Mitochondrial DNA content in eggs as a maternal effect.
  6. Nuclear and mitochondrial DNA editing in human cells with zinc finger deaminases.
  7. Mitoribosomal small subunit maturation involves formation of initiation-like complexes.
  8. The Role of Mitochondrial DNA Mutations in Cardiovascular Diseases.
  9. Genetic interactions of mitochondrial sirtuins in brain tumorigenesis.
  10. HEK293T Cells with TFAM Disruption by CRISPR-Cas9 as a Model for Mitochondrial Regulation.
  11. Mitochondria-Targeted Drug Delivery.
  12. The TFAMoplex-Conversion of the Mitochondrial Transcription Factor A into a DNA Transfection Agent.
  13. Mitochondrial DNA sequence variation and risk of glioma.
  1. Nat Rev Genet. 2022 Jan 21.
    Mitochondrial DNA copy number and disease.
    Dorothy Clyde.
      
    DOI:  https://doi.org/10.1038/s41576-022-00451-2
  2. Life (Basel). 2021 Dec 21. pii: 4. [Epub ahead of print]12(1):
    Molecular Phylogenetics and Mitochondrial Evolution.
    Andrea Luchetti, Federico Plazzi.
      The myth of a "typical" mitochondrial genome (mtDNA) is a rock-hard belief in the field of genetics, at least for the animal kingdom [...].
    DOI:  https://doi.org/10.3390/life12010004
  3. Cell Genom. 2021 Oct 13. pii: 100006. [Epub ahead of print]1(1):
    Association of mitochondrial DNA copy number with cardiometabolic diseases.
    TOPMed mtDNA Working Group in NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
      Mitochondrial DNA (mtDNA) is present in multiple copies in human cells. We evaluated cross-sectional associations of whole blood mtDNA copy number (CN) with several cardiometabolic disease traits in 408,361 participants of multiple ancestries in TOPMed and UK Biobank. Age showed a threshold association with mtDNA CN: among younger participants (<65 years of age), each additional 10 years of age was associated with 0.03 standard deviation (s.d.) higher level of mtDNA CN (P = 0.0014) versus a 0.14 s.d. lower level of mtDNA CN (P = 1.82 × 10-13) among older participants (≥65 years). At lower mtDNA CN levels, we found age-independent associations with increased odds of obesity (P = 5.6 × 10-238), hypertension (P = 2.8 × 10-50), diabetes (P = 3.6 × 10-7), and hyperlipidemia (P = 6.3 × 10-5). The observed decline in mtDNA CN after 65 years of age may be a key to understanding age-related diseases.
    DOI:  https://doi.org/10.1016/j.xgen.2021.100006
  4. Mitochondrion. 2022 Jan 17. pii: S1567-7249(22)00005-8. [Epub ahead of print]63 37-42
    The role of mtDNA haplogroups on metabolic features in narcolepsy type 1.
    Leonardo Caporali, Monica Moresco, Fabio Pizza, Chiara La Morgia, Claudio Fiorini, Daniela Strobbe, Corrado Zenesini, Baharak Hooshiar Kashani, Antonio Torroni, Uberto Pagotto, Valerio Carelli, Giuseppe Plazzi.
      Narcolepsy type 1 (NT1) is due to selective loss of hypocretin (hcrt)-producing-neurons. Hcrt is a neuropeptide regulating the sleep/wake cycle, as well as feeding behavior. A subset of NT1 patients become overweight/obese, with a dysmetabolic phenotype. We hypothesized that mitochondrial DNA (mtDNA) sequence variation might contribute to the metabolic features in NT1 and we undertook an exploratory survey of mtDNA haplogroups in a cohort of well-characterized patients. We studied 246 NT1 Italian patients, fully defined for their metabolic features, including obesity, hypertension, low HDL, hypertriglyceridemia and hyperglycemia. For haplogroup assignment, the mtDNA control region was sequenced in combination with an assessment of diagnostic markers in the coding region. NT1 patients displayed the same mtDNA haplogroups (H, HV, J, K, T, U) frequency as those reported in the general Italian population. The majority of NT1 patients (64%) were overweight: amongst these, 35% were obese, 48% had low HDL cholesterol levels, and 31% had hypertriglyceridemia. We identified an association between haplogroups J, K and hypertriglyceridemia (P = 0.03, 61.5% and 61.5%, respectively vs. 31.3% of the whole sample) and after correction for age and sex, we observed a reduction of these associations (OR = 3.65, 95%CI = 0.76-17.5, p = 0.106 and 1.73, 0.52-5.69, p = 0.368, respectively). The low HDL level showed a trend for association with haplogroup J (P = 0.09, 83.3% vs. 47.4% of the whole sample) and after correction we observed an OR = 6.73, 95%CI = 0.65-69.9, p = 0.110. Our study provides the first indication that mtDNA haplogroups J and K can modulate metabolic features of NT1 patients, linking mtDNA variation to the dysmetabolic phenotype in NT1.
    Keywords:  Haplogroups; Hypertriglyceridemia; Mitochondrial DNA; Narcolepsy
    DOI:  https://doi.org/10.1016/j.mito.2022.01.005
  5. Proc Biol Sci. 2022 Jan 26. 289(1967): 20212100
    Mitochondrial DNA content in eggs as a maternal effect.
    Sin-Yeon Kim, Violette Chiara, Náyade Álvarez-Quintero, Alberto Velando.
      The transmission of detrimental mutations in animal mitochondrial DNA (mtDNA) to the next generation is avoided by a high level of mtDNA content in mature oocytes. Thus, this maternal genetic material has the potential to mediate adaptive maternal effects if mothers change mtDNA level in oocytes in response to their environment or body condition. Here, we show that increased mtDNA abundance in mature oocytes was associated with fast somatic growth during early development but at the cost of increased mortality in three-spined sticklebacks. We also examined whether oocyte mtDNA and sperm DNA damage levels have interacting effects because they can determine the integrity of mitochondrial and nuclear genes in offspring. The level of oxidative DNA damage in sperm negatively affected fertility, but there was no interacting effect of oocyte mtDNA abundance and sperm DNA damage. Oocyte mtDNA level increased towards the end of the breeding season, and the females exposed to warmer temperatures during winter produced eggs with increased mtDNA copies. Our results suggest that oocyte mtDNA level can vary according to the expected energy demands for offspring during embryogenesis and early growth. Thus, mothers can affect offspring development and viability through the context-dependent effects of oocyte mtDNA abundance.
    Keywords:  maternal effect; mitochondria; mtDNA; oocyte; stickleback
    DOI:  https://doi.org/10.1098/rspb.2021.2100
  6. Nat Commun. 2022 Jan 18. 13(1): 366
    Nuclear and mitochondrial DNA editing in human cells with zinc finger deaminases.
    Kayeong Lim, Sung-Ik Cho, Jin-Soo Kim.
      Base editing in nuclear DNA and mitochondrial DNA (mtDNA) is broadly useful for biomedical research, medicine, and biotechnology. Here, we present a base editing platform, termed zinc finger deaminases (ZFDs), composed of custom-designed zinc-finger DNA-binding proteins, the split interbacterial toxin deaminase DddAtox, and a uracil glycosylase inhibitor (UGI), which catalyze targeted C-to-T base conversions without inducing unwanted small insertions and deletions (indels) in human cells. We assemble plasmids encoding ZFDs using publicly available zinc finger resources to achieve base editing at frequencies of up to 60% in nuclear DNA and 30% in mtDNA. Because ZFDs, unlike CRISPR-derived base editors, do not cleave DNA to yield single- or double-strand breaks, no unwanted indels caused by error-prone non-homologous end joining are produced at target sites. Furthermore, recombinant ZFD proteins, expressed in and purified from E. coli, penetrate cultured human cells spontaneously to induce targeted base conversions, demonstrating the proof-of-principle of gene-free gene therapy.
    DOI:  https://doi.org/10.1038/s41467-022-27962-0
  7. Proc Natl Acad Sci U S A. 2022 Jan 18. pii: e2114710118. [Epub ahead of print]119(3):
    Mitoribosomal small subunit maturation involves formation of initiation-like complexes.
    Tea Lenarčič, Moritz Niemann, David J F Ramrath, Salvatore Calderaro, Timo Flügel, Martin Saurer, Marc Leibundgut, Daniel Boehringer, Céline Prange, Elke K Horn, André Schneider, Nenad Ban.
      Mitochondrial ribosomes (mitoribosomes) play a central role in synthesizing mitochondrial inner membrane proteins responsible for oxidative phosphorylation. Although mitoribosomes from different organisms exhibit considerable structural variations, recent insights into mitoribosome assembly suggest that mitoribosome maturation follows common principles and involves a number of conserved assembly factors. To investigate the steps involved in the assembly of the mitoribosomal small subunit (mt-SSU) we determined the cryoelectron microscopy structures of middle and late assembly intermediates of the Trypanosoma brucei mitochondrial small subunit (mt-SSU) at 3.6- and 3.7-Å resolution, respectively. We identified five additional assembly factors that together with the mitochondrial initiation factor 2 (mt-IF-2) specifically interact with functionally important regions of the rRNA, including the decoding center, thereby preventing premature mRNA or large subunit binding. Structural comparison of assembly intermediates with mature mt-SSU combined with RNAi experiments suggests a noncanonical role of mt-IF-2 and a stepwise assembly process, where modular exchange of ribosomal proteins and assembly factors together with mt-IF-2 ensure proper 9S rRNA folding and protein maturation during the final steps of assembly.
    Keywords:  mitochondria; ribosome assembly; structural biology; translation
    DOI:  https://doi.org/10.1073/pnas.2114710118
  8. Int J Mol Sci. 2022 Jan 16. pii: 952. [Epub ahead of print]23(2):
    The Role of Mitochondrial DNA Mutations in Cardiovascular Diseases.
    Siarhei A Dabravolski, Victoria A Khotina, Vasily N Sukhorukov, Vladislav A Kalmykov, Liudmila M Mikhaleva, Alexander N Orekhov.
      Cardiovascular diseases (CVD) are one of the leading causes of morbidity and mortality worldwide. mtDNA (mitochondrial DNA) mutations are known to participate in the development and progression of some CVD. Moreover, specific types of mitochondria-mediated CVD have been discovered, such as MIEH (maternally inherited essential hypertension) and maternally inherited CHD (coronary heart disease). Maternally inherited mitochondrial CVD is caused by certain mutations in the mtDNA, which encode structural mitochondrial proteins and mitochondrial tRNA. In this review, we focus on recently identified mtDNA mutations associated with CVD (coronary artery disease and hypertension). Additionally, new data suggest the role of mtDNA mutations in Brugada syndrome and ischemic stroke, which before were considered only as a result of mutations in nuclear genes. Moreover, we discuss the molecular mechanisms of mtDNA involvement in the development of the disease.
    Keywords:  Brugada syndrome; atherosclerosis; cardiovascular diseases; coronary artery disease; hypertension; ischemic stroke; mitochondria
    DOI:  https://doi.org/10.3390/ijms23020952
  9. Future Oncol. 2022 Jan 17.
    Genetic interactions of mitochondrial sirtuins in brain tumorigenesis.
    Maria Fazal Ul Haq, Mahmood Akhtar Kayani, Taaha Arshad, Raja Abdul Hadi Anwar, Nadia Saeed, Rabia Shafique, Sumaira Fidda Abbasi, Malik Waqar Ahmed, Ishrat Mahjabeen.
      Purpose: The present study was designed to understand the role of expression variations of mitochondrial imported sirtuins in brain tumorigenesis. The expression levels of mitochondrial imported sirtuins were further analyzed for biomarker potential. Methods: Samples from 200 brain tumors and 200 healthy control tissues were used for expression analysis using qPCR and for DNA damage using LORD-Q analysis. Results: Significant deregulation of SIRT3 (p = 0.002), SIRT4 (p = 0.03) and SIRT5 (p = 0.006) was observed in brain tumors versus controls. Co-expression analysis showed a significant correlation between the mitochondrial imported sirtuins versus apoptotic genes. LORD-Q analysis showed a significantly increased frequency of lesions/10 kb of mitochondrial imported sirtuins (p < 0.0001) in brain tumor tissue versus controls. Conclusion: The present study showed a correlation between variations of mitochondrial imported sirtuins and increased brain tumor risk.
    Keywords:  brain tumor; diagnostic/prognostic markers; expression deregulation; mitochondrial imported sirtuins; quantitative PCR
    DOI:  https://doi.org/10.2217/fon-2021-0264
  10. Life (Basel). 2021 Dec 24. pii: 22. [Epub ahead of print]12(1):
    HEK293T Cells with TFAM Disruption by CRISPR-Cas9 as a Model for Mitochondrial Regulation.
    Vanessa Cristina de Oliveira, Kelly Cristine Santos Roballo, Clésio Gomes Mariano Junior, Sarah Ingrid Pinto Santos, Fabiana Fernandes Bressan, Marcos Roberto Chiaratti, Elena J Tucker, Erica E Davis, Jean-Paul Concordet, Carlos Eduardo Ambrósio.
      The mitochondrial transcription factor A (TFAM) is considered a key factor in mitochondrial DNA (mtDNA) copy number. Given that the regulation of active copies of mtDNA is still not fully understood, we investigated the effects of CRISPR-Cas9 gene editing of TFAM in human embryonic kidney (HEK) 293T cells on mtDNA copy number. The aim of this study was to generate a new in vitro model by CRISPR-Cas9 system by editing the TFAM locus in HEK293T cells. Among the resulting single-cell clones, seven had high mutation rates (67-96%) and showed a decrease in mtDNA copy number compared to control. Cell staining with Mitotracker Red showed a reduction in fluorescence in the edited cells compared to the non-edited cells. Our findings suggest that the mtDNA copy number is directly related to TFAM control and its disruption results in interference with mitochondrial stability and maintenance.
    Keywords:  CRISPR-Cas9; HEK293T cells; TFAM; gene editing; mitochondrial DNA
    DOI:  https://doi.org/10.3390/life12010022
  11. Pharmaceutics. 2022 Jan 13. pii: 178. [Epub ahead of print]14(1):
    Mitochondria-Targeted Drug Delivery.
    Joanna Kopecka.
      Mitochondria, organelles surrounded by a double membrane and with their own small genome, are the cells' energy centres [...].
    DOI:  https://doi.org/10.3390/pharmaceutics14010178
  12. Adv Sci (Weinh). 2022 Jan 17. e2104987
    The TFAMoplex-Conversion of the Mitochondrial Transcription Factor A into a DNA Transfection Agent.
    Michael Burger, Seraina Kaelin, Jean-Christophe Leroux.
      Non-viral gene delivery agents, such as cationic lipids, polymers, and peptides, mainly rely on charge-based and hydrophobic interactions for the condensation of DNA molecules into nanoparticles. The human protein mitochondrial transcription factor A (TFAM), on the other hand, has evolved to form nanoparticles with DNA through highly specific protein-protein and protein-DNA interactions. Here, the properties of TFAM are repurposed to create a DNA transfection agent by means of protein engineering. TFAM is covalently fused to Listeria monocytogenes phospholipase C (PLC), an enzyme that lyses lipid membranes under acidic conditions, to enable endosomal escape and human vaccinia-related kinase 1 (VRK1), which is intended to protect the DNA from cytoplasmic defense mechanisms. The TFAM/DNA complexes (TFAMoplexes) are stabilized by cysteine point mutations introduced rationally in the TFAM homodimerization site, resulting in particles, which show maximal activity when formed in 80% serum and transfect HeLa cells in vitro after 30 min of incubation under challenging cell culture conditions. The herein developed TFAM-based DNA scaffolds combine interesting characteristics in an easy-to-use system and can be readily expanded with further protein factors. This makes the TFAMoplex a promising tool in protein-based gene delivery.
    Keywords:  DNA nanoparticles; non-viral gene delivery; protein engineering; protein-based DNA carrier
    DOI:  https://doi.org/10.1002/advs.202104987
  13. Mitochondrion. 2022 Jan 12. pii: S1567-7249(22)00002-2. [Epub ahead of print]63 32-36
    Mitochondrial DNA sequence variation and risk of glioma.
    Claudine M Samanic, Jamie K Teer, Zachary J Thompson, Jordan H Creed, Brooke L Fridley, L Burt Nabors, Sion L Williams, Kathleen M Egan.
       BACKGROUND: Malignant gliomas are the most common primary adult brain tumors, with a poor prognosis and ill-defined etiology. Mitochondrial DNA (mtDNA) sequence variation has been linked with certain cancers; however, research on glioma is lacking.
    METHODS: We examined the association of common (minor allele frequency ≥ 5%) germline mtDNA variants and haplogroups with glioma risk in 1,566 glioma cases and 1,017 controls from a US case-control study, and 425 glioma cases and 1,534 matched controls from the UK Biobank cohort (UKB). DNA samples were genotyped using the UK Biobank array that included a set of common and rare mtDNA variants. Risk associations were examined separately for glioblastoma (GBM) and lower grade tumors (non-GBM).
    RESULTS: In the US study, haplogroup W was inversely associated with glioma when compared with haplogroup H (OR = 0.43, 95%CI: 0.23-0.79); this association was not demonstrated in the UKB (OR = 1.07, 95%CI: 0.47-2.43). In the UKB, the variant m.3010G > A was significantly associated with GBM (OR = 1.32; 95%CI: 1.01-1.73; p = 0.04), but not non-GBM (1.23; 95%CI: 0.78-1.95; p = 0.38); no similar association was observed in the US study. In the US study, the variant m.14798 T > C, was significantly associated with non-GBM (OR = 0.72; 95%CI: 0.53-0.99), but not GBM (OR = 0.86; 95%CI: 0.66-1.11), whereas in the UKB, a positive association was observed between this variant and GBM (OR = 1.46; 95%CI: 1.06-2.02) but not non-GBM (OR = 0.92; 95%CI: 0.52-1.63). None of these associations were significant after adjustment for multiple testing.
    CONCLUSION: The association of inherited mtDNA variation, including rare and singleton variants, with glioma risk merits further study.
    Keywords:  Glioblastoma; Glioma; Mitochondrial DNA; UK Biobank
    DOI:  https://doi.org/10.1016/j.mito.2022.01.002
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