bims-midmar Biomed News
on Mitochondrial DNA maintenance and replication
Issue of 2021‒11‒07
twenty-five papers selected by
Flavia Söllner
Ludwig-Maximilians University
  1. The integrity and assay performance of tissue mitochondrial DNA is considerably affected by choice of isolation method.
  2. Bloom Helicase Along with Recombinase Rad51 Repairs the Mitochondrial Genome of the Malaria Parasite.
  3. Implications of mitochondrial DNA mutations in human induced pluripotent stem cells.
  4. Translation of MT-ATP6 pathogenic variants reveals distinct regulatory consequences from the co-translational quality control of mitochondrial protein synthesis.
  5. Remdesivir; molecular and functional measures of mitochondrial safety.
  6. Mitochondrial DNA methylation drift and postoperative delirium in mice.
  7. First mitochondrial genome wide association study with metabolomics.
  8. Primary mitochondrial myopathies in childhood.
  9. Whole mitochondrial genomes assembled from thermally altered forensic bones and teeth.
  10. Mitochondria-More than just ATP for CTLs.
  11. Mitochondrial-nuclear cross-talk in the human brain is modulated by cell type and perturbed in neurodegenerative disease.
  12. Mitonuclear interactions alter sex-specific longevity in a species without sex chromosomes.
  13. Subcellular Specialization of Mitochondrial Form and Function in Skeletal Muscle Cells.
  14. Mice with disrupted mitochondria used to model Parkinson's disease.
  15. Mitochondrial DNA genetic variants are associated with systemic lupus erythematosus susceptibility, glucocorticoids efficacy, and prognosis.
  16. Use of whole genome sequencing to determine genetic basis of suspected mitochondrial disorders: cohort study.
  17. Blood biomarkers for assessment of mitochondrial dysfunction: An expert review.
  18. Entero-encephalopathy due to FBXL4-related mtDNA depletion syndrome.
  19. Distinct Mitochondrial Remodeling During Mesoderm Differentiation in a Human-Based Stem Cell Model.
  20. Macrophages as Emerging Key Players in Mitochondrial Transfers.
  21. Mitochondrial diseases in South Asia - A Systematic Review.
  22. RNA-directed DNA repair and antibody somatic hypermutation.
  23. Adiponectin receptor agonist AdipoRon blocks skin inflamm-ageing by regulating mitochondrial dynamics.
  24. SARS-CoV-2 and EBV; the cost of a second mitochondrial "whammy"?
  25. Mitochondrial respiration contributes to the interferon gamma response in antigen presenting cells.
  1. Mitochondrion. 2021 Oct 30. pii: S1567-7249(21)00145-8. [Epub ahead of print]
    The integrity and assay performance of tissue mitochondrial DNA is considerably affected by choice of isolation method.
    Bruno Marçal Repolês, Choco Michael Gorospe, Phong Tran, Anna Karin Nilsson, Paulina H Wanrooij.
      The integrity of mitochondrial DNA (mtDNA) isolated from solid tissues is critical for analyses such as long-range PCR, but is typically assessed under conditions that fail to provide information on the individual mtDNA strands. Using denaturing gel electrophoresis, we show that commonly-used isolation procedures generate mtDNA containing several single-strand breaks per strand. Through systematic comparison of DNA isolation methods, we identify a procedure yielding the highest integrity of mtDNA that we demonstrate displays improved performance in downstream assays. Our results highlight the importance of isolation method choice, and serve as a resource to researchers requiring high-quality mtDNA from solid tissues.
    Keywords:  DNA integrity; long-range PCR; mitochondrial DNA; mtDNA; nuclease activity
    DOI:  https://doi.org/10.1016/j.mito.2021.10.005
  2. mSphere. 2021 Nov 03. e0071821
    Bloom Helicase Along with Recombinase Rad51 Repairs the Mitochondrial Genome of the Malaria Parasite.
    Payal Jha, Abhilasha Gahlawat, Sunanda Bhattacharyya, Sandeep Dey, Kota Arun Kumar, Mrinal Kanti Bhattacharyya.
      The homologous recombination (HR) pathway has been implicated as the predominant mechanism for the repair of chromosomal DNA double-strand breaks (DSBs) of the malarial parasite. Although the extrachromosomal mitochondrial genome of this parasite experiences a greater number of DSBs due to its close proximity to the electron transport chain, nothing is known about the proteins involved in the repair of the mitochondrial genome. We investigated the involvement of nucleus-encoded HR proteins in the repair of the mitochondrial genome, as this genome does not code for any DNA repair proteins. Here, we provide evidence that the nucleus-encoded "recombinosome" of the parasite is also involved in mitochondrial genome repair. First, two crucial HR proteins, namely, Plasmodium falciparum Rad51 (PfRad51) and P. falciparum Bloom helicase (PfBlm) are located in the mitochondria. They are recruited to the mitochondrial genome at the schizont stage, a stage that is prone to DSBs due to exposure to various endogenous and physiologic DNA-damaging agents. Second, the recruitment of these two proteins to the damaged mitochondrial genome coincides with the DNA repair kinetics. Moreover, both the proteins exit the mitochondrial DNA (mtDNA) once the genome is repaired. Most importantly, the specific chemical inhibitors of PfRad51 and PfBlm block the repair of UV-induced DSBs of the mitochondrial genome. Additionally, overexpression of these two proteins resulted in a kinetically faster repair. Given the essentiality of the mitochondrial genome, blocking its repair by inhibiting the HR pathway could offer a novel strategy for curbing malaria. IMPORTANCE The impact of malaria on global public health and the world economy continues to surge despite decades of vaccine research and drug development efforts. An alarming rise in resistance toward all the commercially available antimalarial drugs and the lack of an effective malaria vaccine brings us to the urge to identify novel intervention strategies for curbing malaria. Here, we uncover the molecular mechanism behind the repair of the most deleterious form of DNA lesions on the parasitic mitochondrial genome. Given that the single-copy mitochondrion is an indispensable organelle of the malaria parasite, we propose that targeting the mitochondrial DNA repair pathways should be exploited as a potential malaria control strategy. The establishment of the parasitic homologous recombination machinery as the predominant repair mechanism of the mitochondrial DNA double-strand breaks underscores the importance of this pathway as a novel druggable target.
    Keywords:  DNA repair; PfBlm; PfRad51; Plasmodium falciparum; homologous recombination; mitochondria
    DOI:  https://doi.org/10.1128/mSphere.00718-21
  3. Nat Rev Genet. 2021 Nov 02.
    Implications of mitochondrial DNA mutations in human induced pluripotent stem cells.
    Valerio Carelli, Michio Hirano, José Antonio Enríquez, Patrick F Chinnery.
      
    DOI:  https://doi.org/10.1038/s41576-021-00430-z
  4. Hum Mol Genet. 2021 Oct 28. pii: ddab314. [Epub ahead of print]
    Translation of MT-ATP6 pathogenic variants reveals distinct regulatory consequences from the co-translational quality control of mitochondrial protein synthesis.
    Kah Ying Ng, Uwe Richter, Christopher B Jackson, Sara Seneca, Brendan J Battersby.
      Pathogenic variants that disrupt human mitochondrial protein synthesis are associated with a clinically heterogenous group of diseases. Despite an impairment in oxidative phosphorylation being a common phenotype, the underlying molecular pathogenesis is more complex than simply a bioenergetic deficiency. Currently, we have limited mechanistic understanding on the scope by which a primary defect in mitochondrial protein synthesis contributes to organelle dysfunction. Since the proteins encoded in the mitochondrial genome are hydrophobic and need co-translational insertion into a lipid bilayer, responsive quality control mechanisms are required to resolve aberrations that arise with the synthesis of truncated and misfolded proteins. Here, we show that defects in the OXA1L-mediated insertion of MT-ATP6 nascent chains into the mitochondrial inner membrane are rapidly resolved by the AFG3L2 protease complex. Using pathogenic MT-ATP6 variants, we then reveal discrete steps in this quality control mechanism and the differential functional consequences to mitochondrial gene expression. The inherent ability of a given cell type to recognize and resolve impairments in mitochondrial protein synthesis may in part contribute at the molecular level to the wide clinical spectrum of these disorders.
    DOI:  https://doi.org/10.1093/hmg/ddab314
  5. Toxicol Appl Pharmacol. 2021 Nov 02. pii: S0041-008X(21)00387-2. [Epub ahead of print] 115783
    Remdesivir; molecular and functional measures of mitochondrial safety.
    J A Bjork, K B Wallace.
      Remdesivir is one of a few antiviral drugs approved for treating severe cases of coronavirus 2 (SARS-CoV-2) infection in hospitalized patients. The prodrug is a nucleoside analog that interferes with viral replication by inhibiting viral RNA-dependent RNA polymerase. The drug has also been shown to be a weak inhibitor of human mitochondrial RNA polymerase, leaving open the possibility of mitochondrial off-targets and toxicity. The investigation was designed to explore whether remdesivir causes mitochondrial toxicity, using both genomic and functional parameters in the assessment. Human-derived HepG2 liver cells were exposed for up to 48 h in culture to increasing concentrations of remdesivir. At sub-cytotoxic concentrations (<1 μM), the drug failed to alter either the number of copies or the expression of the mitochondrial genome. mtDNA copy number was unaffected as was the relative rates of expression of mtDNA-encoded and nuclear encoded subunits of complexes I and IV of the mitochondrial respiratory chain. Consistent with this is the observation that remdesivir was without effect on mitochondrial respiration, including basal respiration, proton leak, maximum uncoupled respiration, spare respiratory capacity or coupling efficiency. We conclude that although remdesivir has weak inhibitory activity towards mitochondrial RNA polymerase, mitochondria are not primary off-targets for the mechanism of cytotoxicity of the drug.
    Keywords:  COVID; Mitochondria; Off-Target; Remdesivir
    DOI:  https://doi.org/10.1016/j.taap.2021.115783
  6. Eur J Anaesthesiol. 2021 Nov 01.
    Mitochondrial DNA methylation drift and postoperative delirium in mice.
    Yue Liu, Fen Song, Yan Yang, Shuai Yang, Ming Jiang, Wei Zhang, Zhengliang Ma, Xiaoping Gu.
      BACKGROUND: Mitochondrial dysfunction is linked to the etiopathogenesis of postoperative delirium (POD), which severely affects the prognosis of elderly patients undergoing surgery. The methylation of mitochondrial DNA (mtDNA), a new and incompletely described phenomenon that regulates the structure and function of mitochondria, is associated with ageing. However, the relationship between mtDNA methylation and POD has not been established.OBJECTIVE: To explore the potential roles of mitochondrial epigenetic regulation in POD.
    DESIGN: A randomised animal study.
    PARTICIPANTS: Eighty-eight 6-month-old and one hundred seventy-six 18-month-old male C57BL/6N mice.
    INTERVENTIONS: POD was induced by abdominal surgery under 1.4% isoflurane for 2 h. Behavioural tests were performed at 24 h before surgery and at 6, 9 and 24 h after surgery.
    MAIN OUTCOME MEASURES: 5-methylcytosine (5-mC) at five CpG sites of the displacement loop (D-loop) and at 60 CpG sites of coding gene loci in the mitochondrial genome after surgery of the hippocampus, prefrontal cortex, amygdala and anterior cingulate cortex in 6 and 18-month-old mice were detected using bisulfite pyrosequencing. Mitochondrial structure, mitochondrial gene expression and mtDNA copy number were also examined using Electron microscopy and real time PCR to find the association with mtDNA methylation.
    RESULTS: The mtDNA methylation drift manifested as a decrease in the methylation levels at the D-loop and an increase or decrease in the methylation levels at several coding gene loci, ultimately resulting in reduced mtDNA copy numbers, altered mitochondrial gene expression and damaged mitochondrial structures in the hippocampus and prefrontal cortex after surgery. The activation of Silent information regulator-1 (SIRT1) ameliorated anaesthesia-induced and surgery-induced mitochondrial dysfunction and delirium-like behaviours by regulating mtDNA methyltransferase-mediated mtDNA methylation.
    CONCLUSION: These data support the existence of epigenetic mtDNA regulation in POD; however, further studies are required to explore the specific mechanisms.
    TRIAL REGISTRATION: No 20181204 Drum tower hospital.
    DOI:  https://doi.org/10.1097/EJA.0000000000001620
  7. Hum Mol Genet. 2021 Oct 27. pii: ddab312. [Epub ahead of print]
    First mitochondrial genome wide association study with metabolomics.
    Brahim Aboulmaouahib, Gabi Kastenmüller, Karsten Suhre, Sebastian Zöllner, Hansi Weissensteiner, Christian Gieger, Rui Wang-Sattler, Peter Lichtner, Konstantin Strauch, Antònia Flaquer.
      INTRODUCTION: In the era of personalized medicine with more and more patient specific targeted therapies being used, we need reliable, dynamic, faster, and sensitive biomarkers both to track the causes of disease and to develop and evolve therapies during the course of treatment. Metabolomics recently has shown substantial evidence to support its emerging role in disease diagnosis and prognosis. Aside from biomarkers and development of therapies, it is also an important goal to understand the involvement of mitochondrial DNA mtDNA in metabolic regulation, aging, and disease development. Somatic mutations of the mitochondrial genome are also heavily implicated in age-related disease and aging. The general hypothesis is that an alteration in the concentration of metabolite profiles (possibly conveyed by lifestyle and environmental factors) influences the increase of mutation rate in the mtDNA, and thereby contributes to a range of pathophysiological alterations observed in complex diseases.METHODS: We performed an inverted mitochondrial genome wide association analysis between mitochondrial nucleotide variants (mtSNVs) and concentration of metabolites. We used 151 metabolites and the whole sequenced mitochondrial genome from 2718 individuals to identify genetic variants associated with metabolite profiles. Because of the high coverage, next generation sequencing-based analysis of the mitochondrial genome allows for an accurate detection of mitochondrial heteroplasmy and for identification of variants associated with the metabolome.
    RESULTS: The strongest association was found for mt715G > A located in the MT-12SrRNA with the metabolite ratio C2/C10:1 (p-value = 6.82*10-09, β = 0.909). The second most significant mtSNV was found for mt3714A > G located in the MT-ND1 with the metabolite ratio PC ae C42:5/PC ae C44:5 (p-value = 1.02*10-08, β = 3.631). A large number of significant metabolite ratios were observed involving PC aa C36:6 and the variant mt10689G > A, located in the MT-ND4L gene.
    CONCLUSION: These results show an important interconnection between mitochondria and metabolite concentrations. Considering that some of the significant metabolites found in this study have been previously related to complex diseases such as neurological disorders and metabolic conditions, these associations found here might play a crucial role for further investigations of such complex diseases. Understanding the mechanisms that control human health and disease, in particular the role of genetic predispositions and their interaction with environmental factors is a prerequisite for the development of safe and efficient therapies for complex disorders.
    DOI:  https://doi.org/10.1093/hmg/ddab312
  8. Neuromuscul Disord. 2021 Oct;pii: S0960-8966(21)00607-6. [Epub ahead of print]31(10): 978-987
    Primary mitochondrial myopathies in childhood.
    Catarina Olimpio, May Yung Tiet, Rita Horvath.
      Primary mitochondrial myopathies are genetic metabolic disorders of mitochondrial dysfunction affecting mainly, but not exclusively, skeletal muscle. Although individually rare, they are the most common inherited metabolic disorders in childhood. They can be similar to other childhood muscle diseases such as congenital myopathies, dystrophies, myasthenic syndromes or metabolic myopathies and a muscle biopsy and genetic testing are important in the differential diagnosis. Mitochondrial myopathies can present at any age but typically childhood onset myopathies have more significant muscle involvement and are caused by genes encoded in the nuclear DNA. Mitochondrial myopathy in infants presents with hypotonia, muscle weakness and difficulty feeding. In toddlers and older children delayed motor development, exercise intolerance and premature fatigue are common. A number of nuclear DNA and mitochondrial DNA encoded genes are known to cause isolated myopathy in childhood and they are important in a range of mitochondrial functions such as oxidative phosphorylation, mitochondrial transcription/translation and mitochondrial fusion/fission. A rare cause of isolated myopathy in children, reversible infantile respiratory chain deficiency myopathy, is non-progressive and typically associated with spontaneous full recovery. Promising targeted treatments have been reported for a number or mitochondrial myopathies including riboflavin in ACAD9 and ETFDH-myopathies and deoxynucleoside for TK2-related disease.
    Keywords:  Differential diagnosis; Mitochondria; Mitochondrial myopathy; Muscle; Next-generation sequencing; Treatment
    DOI:  https://doi.org/10.1016/j.nmd.2021.08.005
  9. Forensic Sci Int Genet. 2021 Oct 24. pii: S1872-4973(21)00146-0. [Epub ahead of print]56 102610
    Whole mitochondrial genomes assembled from thermally altered forensic bones and teeth.
    M V Emery, K Bolhofner, S Ghafoor, S Winingear, J E Buikstra, L C Fulginiti, A C Stone.
      The recovery and analysis of genetic material obtained from thermally altered human bones and teeth are increasingly important to forensic investigations, especially in cases where soft-tissue identification is no longer possible. Although little is known about how these fire-related processes affect DNA degradation over time, next-generation sequencing technology in combination with traditional osteobiographical applications may provide us clues to these questions. In this study, we compare whole mitochondrial genome data generated using two different DNA extraction methods from 27 thermally altered samples obtained from fire victims (Maricopa County, Arizona) . DNA extracts were converted to double-stranded DNA libraries and enriched for whole mitochondrial DNA (mtDNA) using synthetic biotinylated RNA baits, then sequenced on an Illumina MiSeq. We processed the mitochondrial data using an in-house computational pipeline (MitoPipe1.0) composed of ancient DNA and modern genomics applications, then compared the resulting information across the two extraction types and five burn categories. Our analysis shows that DNA fragmentation increases with temperature, but that the acute insult from fire combined with the lack of water is insufficient to produce 5' and 3' terminal deamination characteristic of ancient DNA. Our data also suggest an acute and significant point of DNA degradation between 350 °C and 550 °C, and that the likelihood of generating high quality mtDNA haplogroup calls decreases significantly at temperatures > 550 °C. This research is part of a concerted effort to understand how fire affects our ability to generate genetic profiles suitable for forensic identification purposes.
    Keywords:  Ancient DNA; Burnt human remains; Cremains; Forensic DNA; Next-generation sequencing; Targeted enrichment; Whole mitochondrial genome
    DOI:  https://doi.org/10.1016/j.fsigen.2021.102610
  10. Sci Immunol. 2021 Nov 05. 6(65): eabn0249
    Mitochondria-More than just ATP for CTLs.
    Jonathan S Maltzman.
      [Figure: see text].
    DOI:  https://doi.org/10.1126/sciimmunol.eabn0249
  11. Commun Biol. 2021 Nov 04. 4(1): 1262
    Mitochondrial-nuclear cross-talk in the human brain is modulated by cell type and perturbed in neurodegenerative disease.
    Aine Fairbrother-Browne, Aminah T Ali, Regina H Reynolds, Sonia Garcia-Ruiz, David Zhang, Zhongbo Chen, Mina Ryten, Alan Hodgkinson.
      Mitochondrial dysfunction contributes to the pathogenesis of many neurodegenerative diseases. The mitochondrial genome encodes core respiratory chain proteins, but the vast majority of mitochondrial proteins are nuclear-encoded, making interactions between the two genomes vital for cell function. Here, we examine these relationships by comparing mitochondrial and nuclear gene expression across different regions of the human brain in healthy and disease cohorts. We find strong regional patterns that are modulated by cell-type and reflect functional specialisation. Nuclear genes causally implicated in sporadic Parkinson's and Alzheimer's disease (AD) show much stronger relationships with the mitochondrial genome than expected by chance, and mitochondrial-nuclear relationships are highly perturbed in AD cases, particularly through synaptic and lysosomal pathways, potentially implicating the regulation of energy balance and removal of dysfunction mitochondria in the etiology or progression of the disease. Finally, we present MitoNuclearCOEXPlorer, a tool to interrogate key mitochondria-nuclear relationships in multi-dimensional brain data.
    DOI:  https://doi.org/10.1038/s42003-021-02792-w
  12. Proc Biol Sci. 2021 Nov 10. 288(1962): 20211813
    Mitonuclear interactions alter sex-specific longevity in a species without sex chromosomes.
    Ben A Flanagan, Ning Li, Suzanne Edmands.
      Impaired mitochondrial function can lead to senescence and the ageing phenotype. Theory predicts degenerative ageing phenotypes and mitochondrial pathologies may occur more frequently in males due to the matrilineal inheritance pattern of mitochondrial DNA observed in most eukaryotes. Here, we estimated the sex-specific longevity for parental and reciprocal F1 hybrid crosses for inbred lines derived from two allopatric Tigriopus californicus populations with over 20% mitochondrial DNA divergence. T. californicus lacks sex chromosomes allowing for more direct testing of mitochondrial function in sex-specific ageing. To better understand the ageing mechanism, we estimated two age-related phenotypes (mtDNA content and 8-hydroxy-20-deoxyguanosine (8-OH-dG) DNA damage) at two time points in the lifespan. Sex differences in lifespan depended on the mitochondrial and nuclear backgrounds, including differences between reciprocal F1 crosses which have different mitochondrial haplotypes on a 50 : 50 nuclear background, with nuclear contributions coming from alternative parents. Young females showed the highest mtDNA content which decreased with age, while DNA damage in males increased with age and exceed that of females 56 days after hatching. The adult sex ratio was male-biased and was attributed to complex mitonuclear interactions. Results thus demonstrate that sex differences in ageing depend on mitonuclear interactions in the absence of sex chromosomes.
    Keywords:  DNA damage; Tigriopus californicus; ageing; hybridization; sex ratio
    DOI:  https://doi.org/10.1098/rspb.2021.1813
  13. Front Cell Dev Biol. 2021 ;9 757305
    Subcellular Specialization of Mitochondrial Form and Function in Skeletal Muscle Cells.
    T Bradley Willingham, Peter T Ajayi, Brian Glancy.
      Across different cell types and within single cells, mitochondria are heterogeneous in form and function. In skeletal muscle cells, morphologically and functionally distinct subpopulations of mitochondria have been identified, but the mechanisms by which the subcellular specialization of mitochondria contributes to energy homeostasis in working muscles remains unclear. Here, we discuss the current data regarding mitochondrial heterogeneity in skeletal muscle cells and highlight potential new lines of inquiry that have emerged due to advancements in cellular imaging technologies.
    Keywords:  bioenergetics; intermyofibrillar mitochondria; mitochondrial connectivity; mitochondrial respiration; organelle interactions; paranuclear mitochondria; paravascular mitochondria; subsarcolemmal mitochondria
    DOI:  https://doi.org/10.3389/fcell.2021.757305
  14. Nature. 2021 Nov 03.
    Mice with disrupted mitochondria used to model Parkinson's disease.
    Zak Doric, Ken Nakamura.
      
    Keywords:  Neurodegeneration; Parkinson's disease
    DOI:  https://doi.org/10.1038/d41586-021-02955-z
  15. Rheumatology (Oxford). 2021 Oct 29. pii: keab806. [Epub ahead of print]
    Mitochondrial DNA genetic variants are associated with systemic lupus erythematosus susceptibility, glucocorticoids efficacy, and prognosis.
    Ying Teng, Zi-Ye Yan, Lin-Lin Wang, Yu-Hua Wang, Ting-Yu Zhang, Zhen Li, Shuang Liu, Jing Cai, Yang-Fan Chen, Mu Li, Sheng-Xiu Liu, Zhou-Zhou Xu, Hai-Liang Huang, Fang Wang, Fa-Ming Pan, Hai-Feng Pan, Hong Su, Yan-Feng Zou.
      OBJECTIVE: To investigate the associations of mitochondrial DNA (mtDNA) genetic variants with systemic lupus erythematosus (SLE) susceptibility, glucocorticoids (GCs) efficacy, and prognosis.METHODS: Our study was done in two stages. First, we performed the whole mitochondrial genome sequencing in 100 patients and 100 controls to initially screen potential mtDNA variants associated with disease and glucocorticoids efficacy. Then, we validated the results in an independent set of samples. In total, 605 SLE patients and 604 normal controls were included in our two-stage study. A two-stage efficacy study was conducted in 512 patients treated with GCs for 12 weeks. We also explored the association between mtDNA variants and SLE prognosis.
    RESULTS: In the combined sample, four mtDNA variants (A4833G, T5108C, G14569A, CA514-515-) were associated with SLE susceptibility (all P  BH<0.05). We confirmed that T16362C was related to GCs efficacy (P  BH=0.014). Significant associations were detected between T16362C and T16519C and the efficacy of GCs in females with SLE (P  BH<0.05). In the prognosis study, variants A4833G (P  BH=0.003) and G14569A (P  BH=9.744 × 1 0 -4) substantially increased SLE relapse risk. Female patients harbouring variants T5108C and T16362C were more prone to relapse (P  BH<0.05). Haplotype analysis showed that haplogroup G was linked with SLE susceptibility (P  BH=0.001) and prognosis (P  BH=0.013). Moreover, mtDNA variants-environment interactions were observed.
    CONCLUSION: We identified novel mtDNA genetic variants that were associated with SLE susceptibility, GCs efficacy, and prognosis. Interactions between mtDNA variants and environmental factors were related to SLE risk and GCs efficacy. Our findings provide important information for future understanding the occurrence and development of SLE.
    Keywords:  genetic variants; glucocorticoids; mitochondrial DNA; prognosis; systemic lupus erythematosus
    DOI:  https://doi.org/10.1093/rheumatology/keab806
  16. BMJ. 2021 11 03. 375 e066288
    Use of whole genome sequencing to determine genetic basis of suspected mitochondrial disorders: cohort study.
    Genomics England Research Consortium
      OBJECTIVE: To determine whether whole genome sequencing can be used to define the molecular basis of suspected mitochondrial disease.DESIGN: Cohort study.
    SETTING: National Health Service, England, including secondary and tertiary care.
    PARTICIPANTS: 345 patients with suspected mitochondrial disorders recruited to the 100 000 Genomes Project in England between 2015 and 2018.
    INTERVENTION: Short read whole genome sequencing was performed. Nuclear variants were prioritised on the basis of gene panels chosen according to phenotypes, ClinVar pathogenic/likely pathogenic variants, and the top 10 prioritised variants from Exomiser. Mitochondrial DNA variants were called using an in-house pipeline and compared with a list of pathogenic variants. Copy number variants and short tandem repeats for 13 neurological disorders were also analysed. American College of Medical Genetics guidelines were followed for classification of variants.
    MAIN OUTCOME MEASURE: Definite or probable genetic diagnosis.
    RESULTS: A definite or probable genetic diagnosis was identified in 98/319 (31%) families, with an additional 6 (2%) possible diagnoses. Fourteen of the diagnoses (4% of the 319 families) explained only part of the clinical features. A total of 95 different genes were implicated. Of 104 families given a diagnosis, 39 (38%) had a mitochondrial diagnosis and 65 (63%) had a non-mitochondrial diagnosis.
    CONCLUSION: Whole genome sequencing is a useful diagnostic test in patients with suspected mitochondrial disorders, yielding a diagnosis in a further 31% after exclusion of common causes. Most diagnoses were non-mitochondrial disorders and included developmental disorders with intellectual disability, epileptic encephalopathies, other metabolic disorders, cardiomyopathies, and leukodystrophies. These would have been missed if a targeted approach was taken, and some have specific treatments.
    DOI:  https://doi.org/10.1136/bmj-2021-066288
  17. Mitochondrion. 2021 Nov 02. pii: S1567-7249(21)00148-3. [Epub ahead of print]
    Blood biomarkers for assessment of mitochondrial dysfunction: An expert review.
    W H G Hubens, A Vallbona-Garcia, I F M de Coo, F H J van Tienen, C A B Webers, H J M Smeets, T G M F Gorgels.
      Although mitochondrial dysfunction is the known cause of primary mitochondrial disease, mitochondrial dysfunction is often difficult to measure and prove, especially when biopsies of affected tissue are not available. In order to identify blood biomarkers of mitochondrial dysfunction, we reviewed studies that measured blood biomarkers in genetically, clinically or biochemically confirmed primary mitochondrial disease patients. In this way, we were certain that there was an underlying mitochondrial dysfunction which could validate the biomarker. We found biomarkers of three classes: 1) functional markers measured in blood cells, 2) biochemical markers of serum/plasma and 3) DNA markers. While none of the reviewed single biomarkers may perfectly reveal all underlying mitochondrial dysfunction, combining biomarkers that cover different aspects of mitochondrial impairment probably is a good strategy. This biomarker panel may assist in the diagnosis of primary mitochondrial disease patients. As mitochondrial dysfunction may also play a significant role in the pathophysiology of multifactorial disorders such as Alzheimer's disease and glaucoma, the panel may serve to assess mitochondrial dysfunction in complex multifactorial diseases as well and enable selection of patients who could benefit from therapies targeting mitochondria.
    Keywords:  Mitochondrial disorder; biomarkers; blood; mitochondrial dysfunction; multifactorial diseases
    DOI:  https://doi.org/10.1016/j.mito.2021.10.008
  18. Turk J Pediatr. 2021 ;pii: 2370. [Epub ahead of print]63(5): 937-939
    Entero-encephalopathy due to FBXL4-related mtDNA depletion syndrome.
    Josef Finsterer.
      
    DOI:  https://doi.org/10.24953/turkjped.2021.05.025
  19. Front Cell Dev Biol. 2021 ;9 744777
    Distinct Mitochondrial Remodeling During Mesoderm Differentiation in a Human-Based Stem Cell Model.
    Sepideh Mostafavi, Novin Balafkan, Ina Katrine Nitschke Pettersen, Gonzalo S Nido, Richard Siller, Charalampos Tzoulis, Gareth J Sullivan, Laurence A Bindoff.
      Given the considerable interest in using stem cells for modeling and treating disease, it is essential to understand what regulates self-renewal and differentiation. Remodeling of mitochondria and metabolism, with the shift from glycolysis to oxidative phosphorylation (OXPHOS), plays a fundamental role in maintaining pluripotency and stem cell fate. It has been suggested that the metabolic "switch" from glycolysis to OXPHOS is germ layer-specific as glycolysis remains active during early ectoderm commitment but is downregulated during the transition to mesoderm and endoderm lineages. How mitochondria adapt during these metabolic changes and whether mitochondria remodeling is tissue specific remain unclear. Here, we address the question of mitochondrial adaptation by examining the differentiation of human pluripotent stem cells to cardiac progenitors and further to differentiated mesodermal derivatives, including functional cardiomyocytes. In contrast to recent findings in neuronal differentiation, we found that mitochondrial content decreases continuously during mesoderm differentiation, despite increased mitochondrial activity and higher levels of ATP-linked respiration. Thus, our work highlights similarities in mitochondrial remodeling during the transition from pluripotent to multipotent state in ectodermal and mesodermal lineages, while at the same time demonstrating cell-lineage-specific adaptations upon further differentiation. Our results improve the understanding of how mitochondrial remodeling and the metabolism interact during mesoderm differentiation and show that it is erroneous to assume that increased OXPHOS activity during differentiation requires a simultaneous expansion of mitochondrial content.
    Keywords:  OXPHOS; cardiomyocyte; development; metabolism; mitochondria; stem cells
    DOI:  https://doi.org/10.3389/fcell.2021.744777
  20. Front Cell Dev Biol. 2021 ;9 747377
    Macrophages as Emerging Key Players in Mitochondrial Transfers.
    Yidan Pang, Changqing Zhang, Junjie Gao.
      Macrophages are a group of heterogeneous cells widely present throughout the body. Under the influence of their specific environments, via both contact and noncontact signals, macrophages integrate into host tissues and contribute to their development and the functions of their constituent cells. Mitochondria are essential organelles that perform intercellular transfers to regulate cell homeostasis. Our review focuses on newly discovered roles of mitochondrial transfers between macrophages and surrounding cells and summarizes emerging functions of macrophages in transmitophagy, metabolic regulation, and immune defense. We also discuss the negative influence of mitochondrial transfers on macrophages, as well as current therapies targeting mitochondria in macrophages. Regulation of macrophages through mitochondrial transfers between macrophages and their surrounding cells is a promising therapy for various diseases, including cardiovascular diseases, inflammatory diseases, obesity, and cancer.
    Keywords:  adipocyte; cardiomyocyte; macrophage; mitochondrial transfer; mitophagy
    DOI:  https://doi.org/10.3389/fcell.2021.747377
  21. Mitochondrion. 2021 Nov 02. pii: S1567-7249(21)00147-1. [Epub ahead of print]
    Mitochondrial diseases in South Asia - A Systematic Review.
    D Hettiarachchi, K Lakmal, V H W Dissanayake.
      BACKGROUND: Mitochondrial diseases are largely underdiagnosed due to their heterogeneity in clinical presentation and genotype. This is especially true for resource-constrained settings in South Asian countries such as Afghanistan, Bangladesh, Bhutan, India, Maldives, Pakistan, Nepal, Sri Lanka and Myanmar. This study aims to evaluate the current status of clinical presentations, diagnosis and treatment of Mitochondrial diseases in the South Asian region.METHODS: We undertook a systematic review of the literature on mitochondrial diseases in the South Asian region. We searched Medline, Pubmed, Cochrane library, and Google scholar using the search terms, "Mitochondrial diseases" AND "Metabolic diseases" (Mesh terms) in the title or the abstract field for each South Asian Country (Afghanistan, Bangladesh, Bhutan, India, Maldives, Pakistan, Nepal, Sri Lanka and Myanmar).
    RESULTS: We found 89 citations in Pubmed, 22 citations in Cochrane library and 68 in Google scholar respectively. A total of 25 non-duplicated studies met the inclusion and exclusion criteria. After assessing the quality of the published studies 18 were included. Which comprised of 17 case reports and one case-control study.
    CONCLUSION: Studies that were published were case reports from India, Pakistan, and Sri Lanka. Due to the paucity of published data on mitochondrial diseases in the South Asian region, it is difficult to estimate its true burden.
    DOI:  https://doi.org/10.1016/j.mito.2021.10.007
  22. Trends Genet. 2021 Nov 02. pii: S0168-9525(21)00289-4. [Epub ahead of print]
    RNA-directed DNA repair and antibody somatic hypermutation.
    Andrew Franklin, Edward J Steele.
      Somatic hypermutation at antibody loci affects both deoxyadenosine-deoxythymidine (A/T) and deoxycytidine-deoxyguanosine (C/G) pairs. Deamination of C to deoxyuridine (U) by activation-induced deaminase (AID) explains how mutation at C/G pairs is potentiated. Mutation at A/T pairs is triggered during the initial stages of repair of AID-generated U lesions and occurs through an as yet unknown mechanism in which polymerase η has a major role. Recent evidence confirms that human polymerase η can act as a reverse transcriptase. Here, we compare the popular suggestion of mutation at A/T pairs through nucleotide mispairing (owing to polymerase error) during short-patch repair synthesis with the alternative proposal of mutation at A/T pairs through RNA editing and RNA-directed DNA repair.
    Keywords:  antibody; polymerase error; polymerase η; reverse transcriptase; somatic hypermutation
    DOI:  https://doi.org/10.1016/j.tig.2021.10.005
  23. Cell Prolif. 2021 Nov 01. e13155
    Adiponectin receptor agonist AdipoRon blocks skin inflamm-ageing by regulating mitochondrial dynamics.
    Jiachen Sun, Xinzhu Liu, Chuan'an Shen, Wen Zhang, Yuezeng Niu.
      INTRODUCTION: Skin is susceptible to senescence-associated secretory phenotype (SASP) and inflamm-ageing partly owing to the degeneration of mitochondria. AdipoRon (AR) has protective effects on mitochondria in metabolic diseases such as diabetes. We explored the role of AR on mitochondria damage induced by skin inflamm-ageing and its underlying mechanism.METHODS: Western blot, immunofluorescence and TUNEL staining were used to detect inflammatory factors and apoptosis during skin ageing. Transmission electron microscopy, ATP determination kit, CellLight Mitochondria GFP (Mito-GFP), mitochondrial stress test, MitoSOX and JC-1 staining were used to detect mitochondrial changes. Western blot was applied to explore the underlying mechanism. Flow cytometry, scratch test, Sulforhodamine B assay and wound healing test were used to detect the effects of AR on cell apoptosis, migration and proliferation.
    RESULTS: AR attenuated inflammatory factors and apoptosis that increased in aged skin, and improved mitochondrial morphology and function. This process at least partly depended on the suppression of dynamin-related protein 1 (Drp1)-mediated excessive mitochondrial division. More specifically, AR up-regulated the phosphorylation of Drp1 at Serine 637 by activating AMP-activated protein kinase (AMPK), thereby inhibiting the mitochondrial translocation of Drp1. Moreover, AR reduced mitochondrial fragmentation and the production of superoxide, preserved the membrane potential and permeability of mitochondria and accelerated wound healing in aged skin.
    CONCLUSION: AR rescues the mitochondria in aged skin by suppressing its excessive division mediated by Drp1.
    Keywords:  AdipoRon; Dynamin-related protein 1 (Drp1); SASP; inflamm-ageing; mitochondria; skin
    DOI:  https://doi.org/10.1111/cpr.13155
  24. Immun Ageing. 2021 Oct 30. 18(1): 40
    SARS-CoV-2 and EBV; the cost of a second mitochondrial "whammy"?
    Alistair V W Nunn, Geoffrey W Guy, Stanley W Botchway, Jimmy D Bell.
      We, and others, have suggested that as the SARS-CoV-2 virus may modulate mitochondrial function, good mitochondrial reserve and health could be key in determining disease severity when exposed to this virus, as the immune system itself is dependent on this organelle's function. With the recent publication of a paper showing that long COVID could be associated with the reactivation of the Epstein Barr Virus, which is well known to manipulate mitochondria, we suggest that this could represent a second mitochondrial "whammy" that might support the mitochondrial hypothesis underlying COVID-19 severity and potentially, the occurrence of longer-term symptoms. As mitochondrial function declines with age, this could be an important factor in why older populations are more susceptible. Key factors which ensure optimal mitochondrial health are generally those that ensure healthy ageing, such as a good lifestyle with plenty of physical activity. The ability of viruses to manipulate mitochondrial function is well described, and it is now also thought that for evolutionary reasons, they also manipulate the ageing process. Given that slowing the ageing process could well be linked to better economic outcomes, the link between mitochondrial health, economics, COVID-19 and other viruses, as well as lifestyle, needs to be considered.
    Keywords:  Ageing; Cost; Epstein Barr Virus; Immunosenescence; Inflammaging; Long COVID; Mitochondria; SARS-CoV-2
    DOI:  https://doi.org/10.1186/s12979-021-00252-x
  25. Elife. 2021 Nov 02. pii: e65109. [Epub ahead of print]10
    Mitochondrial respiration contributes to the interferon gamma response in antigen presenting cells.
    Michael C Kiritsy, Katelyn McCann, Daniel Mott, Stephen M Holland, Samuel M Behar, Christopher M Sassetti, Andrew J Olive.
      The immunological synapse allows antigen presenting cells (APC) to convey a wide array of functionally distinct signals to T cells, which ultimately shape the immune response. The relative effect of stimulatory and inhibitory signals is influenced by the activation state of the APC, which is determined by an interplay between signal transduction and metabolic pathways. While pathways downstream of toll-like receptors rely on glycolytic metabolism for the proper expression of inflammatory mediators, little is known about the metabolic dependencies of other critical signals such as interferon gamma (IFNg). Using CRISPR-Cas9, we performed a series of genome-wide knockout screens in murine macrophages to identify the regulators of IFNg-inducible T cell stimulatory or inhibitory proteins MHCII, CD40, and PD-L1. Our multi-screen approach enabled us to identify novel pathways that control these functionally distinct markers. Further integration of these screening data implicated complex I of the mitochondrial respiratory chain in the expression of all three markers, and by extension the IFNg signaling pathway. We report that the IFNg response requires mitochondrial respiration, and APCs are unable to activate T cells upon genetic or chemical inhibition of complex I. These findings suggest a dichotomous metabolic dependency between IFNg and toll-like receptor signaling, implicating mitochondrial function as a fulcrum of innate immunity.
    Keywords:  human; immunology; inflammation; mouse
    DOI:  https://doi.org/10.7554/eLife.65109
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