bims-midmar Biomed News
on Mitochondrial DNA maintenance and replication
Issue of 2022–04–10
fiveteen papers selected by
Flavia Söllner, Ludwig-Maximilians University
  1. Whole exome sequencing is an alternative method in the diagnosis of mitochondrial DNA diseases.
  2. CRISPR-free base editors with enhanced activity and expanded targeting scope in mitochondrial and nuclear DNA.
  3. Regulation of mitochondrial function by forkhead transcription factors.
  4. Mitochondrial DNA Release Contributes to Intestinal Ischemia/Reperfusion Injury.
  5. Pterostilbene in Combination With Mitochondrial Cofactors Improve Mitochondrial Function in Cellular Models of Mitochondrial Diseases.
  6. Advanced age increases frequencies of de novo mitochondrial mutations in macaque oocytes and somatic tissues.
  7. The SNPs of mitochondrial DNA displacement loop region and mitochondrial DNA copy number associated with risk of polymyositis and dermatomyositis.
  8. Redox Homeostasis in Cardiovascular Disease: The Role of Mitochondrial Sirtuins.
  9. Mitochondrial transfer in BAT.
  10. Dietary restriction modulates mitochondrial DNA damage and oxylipins profile in aged rats.
  11. Gene therapy restores mitochondrial function and protects retinal ganglion cells in optic neuropathy induced by a mito-targeted mutant ND1 gene.
  12. Graph-based models of the Oenothera mitochondrial genome capture the enormous complexity of higher plant mitochondrial DNA organization.
  13. MitoScore, MitoGrade, or MitoSure: what does embryonic mitochondrial deoxyribonucleic acid quantification actually measure and is it useful?
  14. Daily briefing: Most complete human genome yet.
  15. DeepDNAbP: A deep learning-based hybrid approach to improve the identification of deoxyribonucleic acid-binding proteins.
  1. Mol Genet Genomic Med. 2022 Apr 07. e1943
    Whole exome sequencing is an alternative method in the diagnosis of mitochondrial DNA diseases.
    Chong Sun, Shengyang Wu, Ruiguo Chen, Junwu Liu, Jiasen Wang, Yanyun Ma, Zhulin Yuan, Yuezhen Li.
       BACKGROUND: Mitochondrial disease (MD) is genetically a heterogeneous group of disorders with impairment in respiratory chain complexes or pathways associated with the mitochondrial function. Nowadays, it is still a challenge for the genetic screening of MD due to heteroplasmy of mitochondrial genome and the complex model of inheritance. This study was designed to investigate the feasibility of whole exome sequencing (WES)-based testing as an alternative option for the diagnosis of MD.
    METHODS: A Chinese Han cohort of 48 patients with suspect MD features was tested using nanoWES, which was a self-designed WES technique that covered the complete mtDNA genome and 21,019 nuclear genes. Fourteen patients were identified with a single genetic variant and three with single deletion in mtDNA.
    RESULTS: The heteroplasmy levels of variants in mitochondrial genome range from 11% to 100%. NanoWES failed to identify multiple deletions in mtDNA compared with long range PCR and massively parallel sequencing (LR-PCR/MPS). However, our testing showed obvious advantages in identifying variations in nuclear DNA. Based on nanoWES, we identified two patients with nuclear DNA variation. One of them showed Xp22.33-q28 duplication, which indicated a possibility of Klinefelter syndrome.
    CONCLUSION: NanoWES yielded a diagnostic rate of 35.4% for MD. With the rapid advances of next generation sequencing technique and decrease in cost, we recommend the usage of nanoWES as a first-line method in clinical diagnosis.
    Keywords:  genetic diagnosis; mitochondrial disease; next generation sequencing; whole exome sequencing
    DOI:  https://doi.org/10.1002/mgg3.1943
  2. Nat Biotechnol. 2022 Apr 04.
    CRISPR-free base editors with enhanced activity and expanded targeting scope in mitochondrial and nuclear DNA.
    Beverly Y Mok, Anna V Kotrys, Aditya Raguram, Tony P Huang, Vamsi K Mootha, David R Liu.
      The all-protein cytosine base editor DdCBE uses TALE proteins and a double-stranded DNA-specific cytidine deaminase (DddA) to mediate targeted C•G-to-T•A editing. To improve editing efficiency and overcome the strict TC sequence-context constraint of DddA, we used phage-assisted non-continuous and continuous evolution to evolve DddA variants with improved activity and expanded targeting scope. Compared to canonical DdCBEs, base editors with evolved DddA6 improved mitochondrial DNA (mtDNA) editing efficiencies at TC by 3.3-fold on average. DdCBEs containing evolved DddA11 offered a broadened HC (H = A, C or T) sequence compatibility for both mitochondrial and nuclear base editing, increasing average editing efficiencies at AC and CC targets from less than 10% for canonical DdCBE to 15-30% and up to 50% in cell populations sorted to express both halves of DdCBE. We used these evolved DdCBEs to efficiently install disease-associated mtDNA mutations in human cells at non-TC target sites. DddA6 and DddA11 substantially increase the effectiveness and applicability of all-protein base editing.
    DOI:  https://doi.org/10.1038/s41587-022-01256-8
  3. Biochimie. 2022 Mar 31. pii: S0300-9084(22)00079-7. [Epub ahead of print]198 96-108
    Regulation of mitochondrial function by forkhead transcription factors.
    Maria Sona Jerome, Raviprasad Kuthethur, Shama Prasada Kabekkodu, Sanjiban Chakrabarty.
      Mitochondria play a central role in several important cellular processes such as energy production, apoptosis, fatty acid catabolism, calcium regulation, and cellular stress response. Multiple nuclear transcription factors have been reported for their role in the regulation of mitochondrial gene expression. More recently, the role of the forkhead family of transcription factors in various mitochondrial pathways has been reported. Among them, FOXO1, FOXO3a, FOXG1, and FOXM1 have been reported to localize to the mitochondria, of which the first two have been observed to bind to the mitochondrial D-loop. This suggests an important role for forkhead transcription factors in the direct regulation of the mitochondrial genome and function. Forkheads such as FOXO3a, FOXO1, and FOXM1 are involved in the cellular response to oxidative stress, hypoxia, and nutrient limitation. Several members of the forkhead family of transcription factors are also involved in the regulation of nuclear-encoded genes associated with the mitochondrial pathway of apoptosis, respiration, mitochondrial dynamics, and homeostasis.
    Keywords:  Apoptosis; FOXM1; FOXO3a; Forkhead transcription factors; Mitochondria; Mitochondrial dynamics; OXPHOS
    DOI:  https://doi.org/10.1016/j.biochi.2022.03.013
  4. Front Pharmacol. 2022 ;13 854994
    Mitochondrial DNA Release Contributes to Intestinal Ischemia/Reperfusion Injury.
    Shishi Liao, Jie Luo, Tulanisa Kadier, Ke Ding, Rong Chen, Qingtao Meng.
      Mitochondria release many damage-associated molecular patterns (DAMPs) when cells are damaged or stressed, with mitochondrial DNA (mtDNA) being. MtDNA activates innate immune responses and induces inflammation through the TLR-9, NLRP3 inflammasome, and cGAS-STING signaling pathways. Released inflammatory factors cause damage to intestinal barrier function. Many bacteria and endotoxins migrate to the circulatory system and lymphatic system, leading to systemic inflammatory response syndrome (SIRS) and even damaging the function of multiple organs throughout the body. This process may ultimately lead to multiple organ dysfunction syndrome (MODS). Recent studies have shown that various factors, such as the release of mtDNA and the massive infiltration of inflammatory factors, can cause intestinal ischemia/reperfusion (I/R) injury. This destroys intestinal barrier function, induces an inflammatory storm, leads to SIRS, increases the vulnerability of organs, and develops into MODS. Mitophagy eliminates dysfunctional mitochondria to maintain cellular homeostasis. This review discusses mtDNA release during the pathogenesis of intestinal I/R and summarizes methods for the prevention or treatment of intestinal I/R. We also discuss the effects of inflammation and increased intestinal barrier permeability on drugs.
    Keywords:  damage-associated molecular patterns2; inflammation3; intestinal barrier function5; ischemia/reperfusion injury4; mitochondrial DNA1; multiple organ dysfunction syndrome7; systemic inflammatory response syndrome6
    DOI:  https://doi.org/10.3389/fphar.2022.854994
  5. Front Pharmacol. 2022 ;13 862085
    Pterostilbene in Combination With Mitochondrial Cofactors Improve Mitochondrial Function in Cellular Models of Mitochondrial Diseases.
    Juan M Suárez-Rivero, Carmen J Pastor-Maldonado, Ana Romero-González, David Gómez-Fernandez, Suleva Povea-Cabello, Mónica Álvarez-Córdoba, Irene Villalón-García, Marta Talaverón-Rey, Alejandra Suárez-Carrillo, Manuel Munuera-Cabeza, José A Sánchez-Alcázar.
      Mitochondrial diseases are genetic disorders caused by mutations in genes in the nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) that encode mitochondrial structural or functional proteins. Although considered "rare" due to their low incidence, such diseases affect thousands of patients' lives worldwide. Despite intensive research efforts, most mitochondrial diseases are still incurable. Recent studies have proposed the modulation of cellular compensatory pathways such as mitophagy, AMP-activated protein kinase (AMPK) activation or the mitochondrial unfolded protein response (UPRmt) as novel therapeutic approaches for the treatment of these pathologies. UPRmt is an intracellular compensatory pathway that signals mitochondrial stress to the nucleus for the activation of mitochondrial proteostasis mechanisms including chaperones, proteases and antioxidants. In this work a potentially beneficial molecule, pterostilbene (a resveratrol analogue), was identified as mitochondrial booster in drug screenings. The positive effects of pterostilbene were significantly increased in combination with a mitochondrial cocktail (CoC3) consisting of: pterostilbene, nicotinamide, riboflavin, thiamine, biotin, lipoic acid and l-carnitine. CoC3 increases sirtuins' activity and UPRmt activation, thus improving pathological alterations in mutant fibroblasts and induced neurons.
    Keywords:  UPRmt; mitochondrial cofactors; mitochondrial diseases; pterostilbene; sirt3
    DOI:  https://doi.org/10.3389/fphar.2022.862085
  6. Proc Natl Acad Sci U S A. 2022 Apr 12. 119(15): e2118740119
    Advanced age increases frequencies of de novo mitochondrial mutations in macaque oocytes and somatic tissues.
    Barbara Arbeithuber, Marzia A Cremona, James Hester, Alison Barrett, Bonnie Higgins, Kate Anthony, Francesca Chiaromonte, Francisco J Diaz, Kateryna D Makova.
      SignificanceMultiple human genetic diseases are caused by mutations in the maternally transmitted DNA of mitochondria, the powerhouses of the cell. It is important to study how these mutations arise and accumulate with age, especially because humans in many societies now choose to have children at an older age. However, this is difficult to accomplish in humans, particularly for female germline cells, oocytes. To overcome this limitation, we studied mitochondrial mutation origins and accumulation with age in a primate model species, rhesus macaque. We found that new mutations accumulate the fastest in metabolically active liver and the slowest in oocytes. Thus, primate oocytes might have developed a mechanism to protect their mitochondrial DNA from excessive mutations, allowing reproduction later in life.
    Keywords:  duplex sequencing; heteroplasmy; mitochondria; mutations; oocytes
    DOI:  https://doi.org/10.1073/pnas.2118740119
  7. Sci Rep. 2022 Apr 07. 12(1): 5903
    The SNPs of mitochondrial DNA displacement loop region and mitochondrial DNA copy number associated with risk of polymyositis and dermatomyositis.
    Yufei Zhao, Chenxing Peng, Ruixue Lai, Jingjing Zhang, Xiaoyun Zhang, Zhanjun Guo.
      Oxidative damage-induced mitochondrial dysfunction may activate muscle catabolism and autophagy pathways to initiate muscle weakening in idiopathic inflammatory myopathies (IIMs). In this study, Single nucleotide polymorphisms (SNPs) in the mitochondrial displacement loop (D-loop) and mitochondrial DNA (mtDNA) copy number were assessed and their association with the risk of polymyositis and dermatomyositis (PM/DM) was evaluated. Excessive D-loop SNPs (8.779 ± 1.912 vs. 7.972 ± 1.903, p = 0.004) correlated positively with mtDNA copy number (0.602 ± 0.457 vs. 0.300 ± 0.118, p < 0.001). Compared with that of the controls, the mtDNA of PM/DM patients showed D-loop SNP accumulation. In addition, the distribution frequencies of 16304C (p = 0.047) and 16519C (p = 0.043) were significantly higher in the patients with PM/DM. Subsequent analysis showed that reactive oxygen species (ROS) generation was increased in PM/DM patients compared with that in the controls (18,477.756 ± 13,574.916 vs. 14,484.191 ± 5703.097, p = 0.012). Further analysis showed that the PM/DM risk-related allele 16304C was significantly associated with lower IL-4 levels (p = 0.021), while 16519C had a trend to be associated with higher IL-2 expression (p = 0.064). The allele 16519C was associated with a positive antinuclear antibody (ANA) status in PM/DM patients (p = 0.011). Our findings suggest that mitochondrial D-loop SNPs could be potential biomarkers for PM/DM risk and these SNPs associated with cytokine expression may be involved in the development of PM/DM. Further, mtDNA copy number-mediated mitochondrial dysfunction may precede the onset of PM/DM.
    DOI:  https://doi.org/10.1038/s41598-022-09943-x
  8. Front Endocrinol (Lausanne). 2022 ;13 858330
    Redox Homeostasis in Cardiovascular Disease: The Role of Mitochondrial Sirtuins.
    Alberto Zullo, Rosa Guida, Rosaria Sciarrillo, Francesco P Mancini.
      Cardiovascular disease (CVD) is still the leading cause of death worldwide. Despite successful advances in both pharmacological and lifestyle strategies to fight well-established risk factors, the burden of CVD is still increasing. Therefore, it is necessary to further deepen our knowledge of the pathogenesis of the disease for developing novel therapies to limit even more its related morbidity and mortality. Oxidative stress has been identified as a common trait of several manifestations of CVD and could be a promising target for innovative treatments. Mitochondria are a major source of oxidative stress and sirtuins are a family of enzymes that generate different post-translational protein modifications, thus regulating important cellular processes, including cell cycle, autophagy, gene expression, and others. In particular, three sirtuins, SIRT3, SIRT4, and SIRT5 are located within the mitochondrial matrix where they regulate energy production and antioxidant pathways. Therefore, these sirtuins are strongly involved in the balance between oxidant and antioxidant mechanisms. In this review, we summarize the activities of these sirtuins with a special focus on their role in the control of oxidative stress, in relation to energy metabolism, atherosclerosis, and CVD.
    Keywords:  ROS; cardiovascular disease; energy metabolism; mitochondria; sirtuins
    DOI:  https://doi.org/10.3389/fendo.2022.858330
  9. Nat Rev Endocrinol. 2022 Apr 07.
    Mitochondrial transfer in BAT.
    Shimona Starling.
      
    DOI:  https://doi.org/10.1038/s41574-022-00674-7
  10. FEBS J. 2022 Apr 03.
    Dietary restriction modulates mitochondrial DNA damage and oxylipins profile in aged rats.
    Artem P Gureev, Nadezda V Andrianova, Irina B Pevzner, Ljubava D Zorova, Ekaterina V Chernyshova, Irina S Sadovnikova, Dmitry V Chistyakov, Vasily A Popkov, Dmitry S Semenovich, Valentina A Babenko, Denis N Silachev, Dmitry B Zorov, Egor Y Plotnikov, Vasily N Popov.
      Age-related impairment of coordination of the processes of maintaining mitochondrial homeostasis is associated with a decrease in the functionality of cells and leads to degenerative processes. Mitochondrial DNA (mtDNA) can be a marker of oxidative stress and tissue degeneration. However, the mechanism of accumulation of age-related damage in mtDNA remains unclear. In this study, we analyzed the accumulation of mtDNA damage in several organs of rats during aging, as well as the possibility of reversing these alterations by dietary restriction (DR). We showed that mtDNA of brain compartments (with the exception of the cerebellum), along with kidney mtDNA, was the most susceptible to accumulation of age-related damage, while liver, testis, and lung were the least susceptible organs. DR prevented age-related accumulation of mtDNA damage in the cortex and led to its decrease in the lung and testis. Changes in mtDNA copy number and expression of genes involved in the regulation of mitochondrial biogenesis and mitophagy were also tissue-specific. There was a tendency for an age-related decrease in the copy number of mtDNA in the striatum and its increase in the kidney. DR promoted an increase in the amount of mtDNA in the cerebellum and hippocampus. mtDNA damage may be associated not only with the metabolic activity of organs but also with the lipid composition and activity of processes associated with the isoprostanes pathway of lipid peroxidation. The comparison of polyunsaturated fatty acids (PUFAs) and oxylipins profiles in old rats showed that DR decreased the synthesis of arachidonic acid and its metabolites synthesized by the cyclooxygenase (COX), cytochrome P450 monooxygenases (CYP), and lipoxygenase (LOX) metabolic pathways.
    Keywords:  caloric restriction; mitochondria; oxidative stress; oxylipins; quality control
    DOI:  https://doi.org/10.1111/febs.16451
  11. Gene Ther. 2022 Apr 06.
    Gene therapy restores mitochondrial function and protects retinal ganglion cells in optic neuropathy induced by a mito-targeted mutant ND1 gene.
    Yuan Liu, Jeremy D Eastwood, Diego E Alba, Sindhu Velmurugan, Ning Sun, Vittorio Porciatti, Richard K Lee, William W Hauswirth, John Guy, Hong Yu.
      Therapies for genetic disorders caused by mutated mitochondrial DNA are an unmet need, in large part due barriers in delivering DNA to the organelle and the absence of relevant animal models. We injected into mouse eyes a mitochondrially targeted Adeno-Associated-Virus (MTS-AAV) to deliver the mutant human NADH ubiquinone oxidoreductase subunit I (hND1/m.3460 G > A) responsible for Leber's hereditary optic neuropathy, the most common primary mitochondrial genetic disease. We show that the expression of the mutant hND1 delivered to retinal ganglion cells (RGC) layer colocalizes with the mitochondrial marker PORIN and the assembly of the expressed hND1 protein into host respiration complex I. The hND1-injected eyes exhibit hallmarks of the human disease with progressive loss of RGC function and number, as well as optic nerve degeneration. We also show that gene therapy in the hND1 eyes by means of an injection of a second MTS-AAV vector carrying wild-type human ND1 restores mitochondrial respiratory complex I activity, the rate of ATP synthesis and protects RGCs and their axons from dysfunction and degeneration. These results prove that MTS-AAV is a highly efficient gene delivery approach with the ability to create mito-animal models and has the therapeutic potential to treat mitochondrial genetic diseases.
    DOI:  https://doi.org/10.1038/s41434-022-00333-6
  12. NAR Genom Bioinform. 2022 Jun;4(2): lqac027
    Graph-based models of the Oenothera mitochondrial genome capture the enormous complexity of higher plant mitochondrial DNA organization.
    Axel Fischer, Jana Dotzek, Dirk Walther, Stephan Greiner.
      Plant mitochondrial genomes display an enormous structural complexity, as recombining repeat-pairs lead to the generation of various sub-genomic molecules, rendering these genomes extremely challenging to assemble. We present a novel bioinformatic data-processing pipeline called SAGBAC (Semi-Automated Graph-Based Assembly Curator) that identifies recombinogenic repeat-pairs and reconstructs plant mitochondrial genomes. SAGBAC processes assembly outputs and applies our novel ISEIS (Iterative Sequence Ends Identity Search) algorithm to obtain a graph-based visualization. We applied this approach to three mitochondrial genomes of evening primrose (Oenothera), a plant genus used for cytoplasmic genetics studies. All identified repeat pairs were found to be flanked by two alternative and unique sequence-contigs defining so-called 'double forks', resulting in four possible contig-repeat-contig combinations for each repeat pair. Based on the inferred structural models, the stoichiometry of the different contig-repeat-contig combinations was analyzed using Illumina mate-pair and PacBio RSII data. This uncovered a remarkable structural diversity of the three closely related mitochondrial genomes, as well as substantial phylogenetic variation of the underlying repeats. Our model allows predicting all recombination events and, thus, all possible sub-genomes. In future work, the proposed methodology may prove useful for the investigation of the sub-genome organization and dynamics in different tissues and at various developmental stages.
    DOI:  https://doi.org/10.1093/nargab/lqac027
  13. F S Rep. 2022 Mar;3(1): 1-2
    MitoScore, MitoGrade, or MitoSure: what does embryonic mitochondrial deoxyribonucleic acid quantification actually measure and is it useful?
    Richard J Paulson.
      
    DOI:  https://doi.org/10.1016/j.xfre.2022.02.001
  14. Nature. 2022 Apr 01.
    Daily briefing: Most complete human genome yet.
    Flora Graham.
      
    DOI:  https://doi.org/10.1038/d41586-022-00963-1
  15. Comput Biol Med. 2022 Mar 30. pii: S0010-4825(22)00225-6. [Epub ahead of print]145 105433
    DeepDNAbP: A deep learning-based hybrid approach to improve the identification of deoxyribonucleic acid-binding proteins.
    Md Faruk Hosen, S M Hasan Mahmud, Kawsar Ahmed, Wenyu Chen, Mohammad Ali Moni, Hong-Wen Deng, Watshara Shoombuatong, Md Mehedi Hasan.
      Accurate identification of DNA-binding proteins (DBPs) is critical for both understanding protein function and drug design. DBPs also play essential roles in different kinds of biological activities such as DNA replication, repair, transcription, and splicing. As experimental identification of DBPs is time-consuming and sometimes biased toward prediction, constructing an effective DBP model represents an urgent need, and computational methods that can accurately predict potential DBPs based on sequence information are highly desirable. In this paper, a novel predictor called DeepDNAbP has been developed to accurately predict DBPs from sequences using a convolutional neural network (CNN) model. First, we perform three feature extraction methods, namely position-specific scoring matrix (PSSM), pseudo-amino acid composition (PseAAC) and tripeptide composition (TPC), to represent protein sequence patterns. Secondly, SHapley Additive exPlanations (SHAP) are employed to remove the redundant and irrelevant features for predicting DBPs. Finally, the best features are provided to the CNN classifier to construct the DeepDNAbP model for identifying DBPs. The final DeepDNAbP predictor achieves superior prediction performance in K-fold cross-validation tests and outperforms other existing predictors of DNA-protein binding methods. DeepDNAbP is poised to be a powerful computational resource for the prediction of DBPs. The web application and curated datasets in this study are freely available at: http://deepdbp.sblog360.blog/.
    Keywords:  DNA-binding protein; Feature encoding; SHapley additive exPlanations and CNN
    DOI:  https://doi.org/10.1016/j.compbiomed.2022.105433
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