bims-midmar Biomed News
on Mitochondrial DNA maintenance and replication
Issue of 2021‒11‒21
eleven papers selected by
Flavia Söllner
Ludwig-Maximilians University
  1. Autism spectrum disorder: A mitochondrial disorder.
  2. Metabolic resistance to the inhibition of mitochondrial transcription revealed by CRISPR-Cas9 screen.
  3. Cardiovascular Involvement in mtDNA Disease: Diagnosis, Management, and Therapeutic Options.
  4. Balancing of mitochondrial translation through METTL8-mediated m3C modification of mitochondrial tRNAs.
  5. Papillary thyroid carcinoma tall cell variant shares accumulation of mitochondria, mitochondrial DNA mutations, and loss of oxidative phosphorylation complex I integrity with oncocytic tumors.
  6. Whole-Exome Sequencing Identifies a Novel POLG Frameshift Variant in an Adult Patient Presenting with Progressive External Ophthalmoplegia and Mitochondrial DNA Depletion.
  7. Widespread use of unconventional targeting signals in mitochondrial ribosome proteins.
  8. Telomere length and mitochondrial DNA copy number in multidrug-resistant tuberculosis.
  9. Age-related changes in the energy of human mesenchymal stem cells.
  10. mtDNA in the Pathogenesis of Cardiovascular Diseases.
  11. The metabolic growth limitations of petite cells lacking the mitochondrial genome.
  1. Iran J Child Neurol. 2021 ;15(4): 115-117
    Autism spectrum disorder: A mitochondrial disorder.
    Josef Finsterer.
      
    Keywords:  Abnormal behaviour; Autism; MTDNA; Mitochondrial; Respiratory Chain
    DOI:  https://doi.org/10.22037/ijcn.v16i2.33066
  2. EMBO Rep. 2021 Nov 15. e53054
    Metabolic resistance to the inhibition of mitochondrial transcription revealed by CRISPR-Cas9 screen.
    Mara Mennuni, Roberta Filograna, Andrea Felser, Nina A Bonekamp, Patrick Giavalisco, Oleksandr Lytovchenko, Nils-Göran Larsson.
      Cancer cells depend on mitochondria to sustain their increased metabolic need and mitochondria therefore constitute possible targets for cancer treatment. We recently developed small-molecule inhibitors of mitochondrial transcription (IMTs) that selectively impair mitochondrial gene expression. IMTs have potent antitumor properties in vitro and in vivo, without affecting normal tissues. Because therapy-induced resistance is a major constraint to successful cancer therapy, we investigated mechanisms conferring resistance to IMTs. We employed a CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats)-(CRISP-associated protein 9) whole-genome screen to determine pathways conferring resistance to acute IMT1 treatment. Loss of genes belonging to von Hippel-Lindau (VHL) and mammalian target of rapamycin complex 1 (mTORC1) pathways caused resistance to acute IMT1 treatment and the relevance of these pathways was confirmed by chemical modulation. We also generated cells resistant to chronic IMT treatment to understand responses to persistent mitochondrial gene expression impairment. We report that IMT1-acquired resistance occurs through a compensatory increase of mitochondrial DNA (mtDNA) expression and cellular metabolites. We found that mitochondrial transcription factor A (TFAM) downregulation and inhibition of mitochondrial translation impaired survival of resistant cells. The identified susceptibility and resistance mechanisms to IMTs may be relevant for different types of mitochondria-targeted therapies.
    Keywords:  CRISPR-Cas9 screen; cancer; chemoresistance; inhibitor of mitochondrial transcription; mtDNA
    DOI:  https://doi.org/10.15252/embr.202153054
  3. Heart Fail Clin. 2022 Jan;pii: S1551-7136(21)00072-6. [Epub ahead of print]18(1): 51-60
    Cardiovascular Involvement in mtDNA Disease: Diagnosis, Management, and Therapeutic Options.
    Michele Lioncino, Emanuele Monda, Martina Caiazza, Adelaide Fusco, Annapaola Cirillo, Francesca Dongiglio, Vicenzo Simonelli, Simone Sampaolo, Lucia Ruggiero, Gioacchino Scarano, Vicenzo Pota, Giulia Frisso, Cristina Mazzaccara, Giulia D'Amati, Gerardo Nigro, Maria Giovanna Russo, Karim Wahbi, Giuseppe Limongelli.
      Mitochondrial diseases (MD) include an heterogenous group of systemic disorders caused by sporadic or inherited mutations in nuclear or mitochondrial DNA (mtDNA), causing impairment of oxidative phosphorylation system. Hypertrophic cardiomyopathy is the dominant pattern of cardiomyopathy in all forms of mtDNA disease, being observed in almost 40% of the patients. Dilated cardiomyopathy, left ventricular noncompaction, and conduction system disturbances have been also reported. In this article, the authors discuss the current clinical knowledge on MD, focusing on diagnosis and management of mitochondrial diseases caused by mtDNA mutations.
    Keywords:  Hypertrophic cardiomyopathy; MELAS syndrome; Mitochondrial diseases; mtDNA
    DOI:  https://doi.org/10.1016/j.hfc.2021.07.003
  4. Mol Cell. 2021 Nov 08. pii: S1097-2765(21)00910-2. [Epub ahead of print]
    Balancing of mitochondrial translation through METTL8-mediated m3C modification of mitochondrial tRNAs.
    Eva Schöller, James Marks, Virginie Marchand, Astrid Bruckmann, Christopher A Powell, Markus Reichold, Christian Daniel Mutti, Katja Dettmer, Regina Feederle, Stefan Hüttelmaier, Mark Helm, Peter Oefner, Michal Minczuk, Yuri Motorin, Markus Hafner, Gunter Meister.
      Mitochondria contain a specific translation machinery for the synthesis of mitochondria-encoded respiratory chain components. Mitochondrial tRNAs (mt-tRNAs) are also generated from the mitochondrial DNA and, similar to their cytoplasmic counterparts, are post-transcriptionally modified. Here, we find that the RNA methyltransferase METTL8 is a mitochondrial protein that facilitates 3-methyl-cytidine (m3C) methylation at position C32 of the mt-tRNASer(UCN) and mt-tRNAThr. METTL8 knockout cells show a reduction in respiratory chain activity, whereas overexpression increases activity. In pancreatic cancer, METTL8 levels are high, which correlates with lower patient survival and an enhanced respiratory chain activity. Mitochondrial ribosome profiling uncovered mitoribosome stalling on mt-tRNASer(UCN)- and mt-tRNAThr-dependent codons. Further analysis of the respiratory chain complexes using mass spectrometry revealed reduced incorporation of the mitochondrially encoded proteins ND6 and ND1 into complex I. The well-balanced translation of mt-tRNASer(UCN)- and mt-tRNAThr-dependent codons through METTL8-mediated m3C32 methylation might, therefore, facilitate the optimal composition and function of the mitochondrial respiratory chain.
    Keywords:  METTL8; RNA modification; m(3)C; mt-tRNA; translation
    DOI:  https://doi.org/10.1016/j.molcel.2021.10.018
  5. J Pathol Clin Res. 2021 Nov 17.
    Papillary thyroid carcinoma tall cell variant shares accumulation of mitochondria, mitochondrial DNA mutations, and loss of oxidative phosphorylation complex I integrity with oncocytic tumors.
    Oleksiy Tsybrovskyy, Monica De Luise, Dario de Biase, Leonardo Caporali, Claudio Fiorini, Giuseppe Gasparre, Valerio Carelli, Dominik Hackl, Larisa Imamovic, Silke Haim, Manuel Sobrinho-Simões, Giovanni Tallini.
      Papillary thyroid carcinoma tall cell variant (PTC-TCV), a form of PTC regarded as an aggressive subtype, shares several morphologic features with oncocytic tumors. Pathogenic homoplasmic/highly heteroplasmic somatic mitochondrial DNA (mtDNA) mutations, usually affecting oxidative phosphorylation (OXPHOS) complex I subunits, are hallmarks of oncocytic cells. To clarify the relationship between PTC-TCV and oncocytic thyroid tumors, 17 PTC-TCV and 16 PTC non-TCV controls (cPTC) were subjected to: (1) transmission electron microscopy (TEM) to assess mitochondria accumulation, (2) next-generation sequencing to analyze mtDNA and nuclear genes frequently mutated in thyroid carcinoma, and (3) immunohistochemistry (IHC) for prohibitin and complex I subunit NDUFS4 to evaluate OXPHOS integrity. TEM showed replacement of cytoplasm by mitochondria in PTC-TCV but not in cPTC cells. All 17 PTC-TCV had at least one mtDNA mutation, totaling 21 mutations; 3/16 cPTC (19%) had mtDNA mutations (p < 0.001). PTC-TCV mtDNA mutations were homoplasmic/highly heteroplasmic, 16/21 (76%) mapping within mtDNA-encoded complex I subunits. MtDNA mutations in cPTC were homoplasmic in 2 cases and at low heteroplasmy in the third case, 2/3 mapping to mtDNA-encoded complex I subunits; 2/3 cPTC with mtDNA mutations had small tall cell subpopulations. PTC-TCV showed strong prohibitin expression and cPTC low-level expression, consistent with massive and limited mitochondrial content, respectively. All 17 PTC-TCV showed NDUFS4 loss (partial or complete) and 3 of 16 cPTC (19%) had (partial) NDUFS4 loss, consistent with lack of complex I integrity in PTC-TCV (p < 0.001). IHC loss of NDUFS4 was associated with mtDNA mutations (p < 0.001). Four BRAF V600E mutated PTCs had loss of NDUSF4 expression limited to neoplastic cell subpopulations with tall cell features, indicating that PTCs first acquire BRAF V600E and then mtDNA mutations. Similar to oncocytic thyroid tumors, PTC-TCV is characterized by mtDNA mutations, massive accumulation of mitochondria, and loss of OXPHOS integrity. IHC loss of NDUFS-4 can be used as a surrogate marker for OXPHOS disruption and to reliably diagnose PTC-TCV.
    Keywords:  BRAF V600E; mitochondria; mitochondrial DNA mutations; oncocytic tumors; papillary thyroid carcinoma; tall cell variant papillary carcinoma; thyroid tumor diagnosis
    DOI:  https://doi.org/10.1002/cjp2.247
  6. Case Rep Genet. 2021 ;2021 9969071
    Whole-Exome Sequencing Identifies a Novel POLG Frameshift Variant in an Adult Patient Presenting with Progressive External Ophthalmoplegia and Mitochondrial DNA Depletion.
    Justin Kurtz, Joseph Americo Fernandes, Mahesh Mansukhani, William C Copeland, Ali B Naini.
      Mitochondrial DNA (mtDNA) depletion syndromes are a group of autosomal recessive disorders associated with a spectrum of clinical diseases, which include progressive external ophthalmoplegia (PEO). They are caused by variants in nuclear DNA (nDNA) encoded genes, and the gene that encodes for mtDNA polymerase gamma (POLG) is commonly involved. A splice-site mutation in POLG, c.3104+3A > T, was previously identified in three families with findings of PEO, and studies demonstrated this variant to result in skipping of exon 19. Here, we report a 57-year-old female who presented with ophthalmoplegia, ptosis, muscle weakness, and exercise intolerance with a subsequent muscle biopsy demonstrating mitochondrial myopathy on histopathologic evaluation and multiple mtDNA deletions by southern blot analysis. Whole-exome sequencing identified the previously characterized c. 3104+3A > T splice-site mutation in compound heterozygosity with a novel frameshift variant, p.Gly23Serfs ∗ 236 (c.67_88del). mtDNA copy number analysis performed on the patient's muscle showed mtDNA depletion, as expected in a patient with biallelic pathogenic mutations in POLG. This is the first reported case with POLG p.Gly23Serfs ∗ 236, discovered in a patient presenting with features of PEO.
    DOI:  https://doi.org/10.1155/2021/9969071
  7. EMBO J. 2021 Nov 17. e109519
    Widespread use of unconventional targeting signals in mitochondrial ribosome proteins.
    Yury S Bykov, Tamara Flohr, Felix Boos, Naama Zung, Johannes M Herrmann, Maya Schuldiner.
      Mitochondrial ribosomes are complex molecular machines indispensable for respiration. Their assembly involves the import of several dozens of mitochondrial ribosomal proteins (MRPs), encoded in the nuclear genome, into the mitochondrial matrix. Proteomic and structural data as well as computational predictions indicate that up to 25% of yeast MRPs do not have a conventional N-terminal mitochondrial targeting signal (MTS). We experimentally characterized a set of 15 yeast MRPs in vivo and found that five use internal MTSs. Further analysis of a conserved model MRP, Mrp17/bS6m, revealed the identity of the internal targeting signal. Similar to conventional MTS-containing proteins, the internal sequence mediates binding to TOM complexes. The entire sequence of Mrp17 contains positive charges mediating translocation. The fact that these sequence properties could not be reliably predicted by standard methods shows that mitochondrial protein targeting is more versatile than expected. We hypothesize that structural constraints imposed by ribosome assembly interfaces may have disfavored N-terminal presequences and driven the evolution of internal targeting signals in MRPs.
    Keywords:  mitochondria; mitochondrial ribosome; mitochondrial targeting signal; targeting; translocation
    DOI:  https://doi.org/10.15252/embj.2021109519
  8. Tuberculosis (Edinb). 2021 Nov 10. pii: S1472-9792(21)00094-9. [Epub ahead of print]131 102144
    Telomere length and mitochondrial DNA copy number in multidrug-resistant tuberculosis.
    Lauma Freimane, Linda Barkane, Viktorija Igumnova, Agnija Kivrane, Egija Zole, Renate Ranka.
      Multidrug resistant tuberculosis (MDR-TB) is a severe disease that requires prolonged chemotherapy and is associated with an increased probability of treatment failure and death. MDR-TB is a state of heightened oxidative stress and inflammation, which could be related to the aging-related processes and immunosenescence. We, therefore, tested the hypothesis that MDR-TB is associated with alterations in aging biomarkers in peripheral blood cells. We investigated 51 MDR-TB patients and 57 healthy individuals and carried out an analysis of covariance to assess the possible impact of different variables on biomarker perturbations. The results showed that MDR-TB patients had significantly reduced telomere length (TL) and increased mitochondrial DNA copy number (mtDNA CN) (P < 0.05) in comparison to the controls, and MDR-TB infection was the main influencing factor. Male sex and extrapulmonary TB strongly influenced mtDNA CN increment, and MDR-TB patients with normal weight had longer telomeres than those who were underweight (P < 0.05). In conclusion, the evidence for shorter telomeres and higher mtDNA CN in the peripheral blood cells of MDR-TB patients was obtained indicating the connection between MDR-TB and aging biomarkers. The observed associations highlight a complicated interplay between MDR-TB and immunosenescence, thus further studies are required to achieve full understanding.
    Keywords:  Aging biomarkers; Immunosenescence; Multidrug resistant tuberculosis
    DOI:  https://doi.org/10.1016/j.tube.2021.102144
  9. J Cell Physiol. 2021 Nov 17.
    Age-related changes in the energy of human mesenchymal stem cells.
    Mario Barilani, Christopher Lovejoy, Roberta Piras, Andrey Y Abramov, Lorenza Lazzari, Plamena R Angelova.
      Aging is a physiological process that leads to a higher risk for the most devastating diseases. There are a number of theories of human aging proposed, and many of them are directly or indirectly linked to mitochondria. Here, we used mesenchymal stem cells (MSCs) from young and older donors to study age-related changes in mitochondrial metabolism. We have found that aging in MSCs is associated with a decrease in mitochondrial membrane potential and lower NADH levels in mitochondria. Mitochondrial DNA content is higher in aged MSCs, but the overall mitochondrial mass is decreased due to increased rates of mitophagy. Despite the higher level of ATP in aged cells, a higher rate of ATP consumption renders them more vulnerable to energy deprivation compared to younger cells. Changes in mitochondrial metabolism in aged MSCs activate the overproduction of reactive oxygen species in mitochondria which is compensated by a higher level of the endogenous antioxidant glutathione. Thus, energy metabolism and redox state are the drivers for the aging of MSCs/mesenchymal stromal cells.
    Keywords:  MSC; aging; bioenergetics; bone marrow; cellular senescence; mitochondria
    DOI:  https://doi.org/10.1002/jcp.30638
  10. Dis Markers. 2021 ;2021 7157109
    mtDNA in the Pathogenesis of Cardiovascular Diseases.
    Lili Wang, Qianhui Zhang, Kexin Yuan, Jing Yuan.
      The incidence rate of cardiovascular disease (CVD) has been increasing year by year and has become the main cause for the increase of mortality. Mitochondrial DNA (mtDNA) plays a crucial role in the pathogenesis of CVD, especially in heart failure and ischemic heart diseases. With the deepening of research, more and more evidence showed that mtDNA is related to the occurrence and development of CVD. Current studies mainly focus on how mtDNA copy number, an indirect biomarker of mitochondrial function, contributes to CVD and its underlying mechanisms including mtDNA autophagy, the effect of mtDNA on cardiac inflammation, and related metabolic functions. However, no relevant studies have been conducted yet. In this paper, we combed the current research status of the mechanism related to the influence of mtDNA on the occurrence, development, and prognosis of CVD, so as to find whether these mechanisms have something in common, or is there a correlation between each mechanism for the development of CVD?
    DOI:  https://doi.org/10.1155/2021/7157109
  11. Nat Metab. 2021 Nov;3(11): 1521-1535
    The metabolic growth limitations of petite cells lacking the mitochondrial genome.
    Jakob Vowinckel, Johannes Hartl, Hans Marx, Martin Kerick, Kathrin Runggatscher, Markus A Keller, Michael Mülleder, Jason Day, Manuela Weber, Mark Rinnerthaler, Jason S L Yu, Simran Kaur Aulakh, Andrea Lehmann, Diethard Mattanovich, Bernd Timmermann, Nianshu Zhang, Cory D Dunn, James I MacRae, Michael Breitenbach, Markus Ralser.
      Eukaryotic cells can survive the loss of their mitochondrial genome, but consequently suffer from severe growth defects. 'Petite yeasts', characterized by mitochondrial genome loss, are instrumental for studying mitochondrial function and physiology. However, the molecular cause of their reduced growth rate remains an open question. Here we show that petite cells suffer from an insufficient capacity to synthesize glutamate, glutamine, leucine and arginine, negatively impacting their growth. Using a combination of molecular genetics and omics approaches, we demonstrate the evolution of fast growth overcomes these amino acid deficiencies, by alleviating a perturbation in mitochondrial iron metabolism and by restoring a defect in the mitochondrial tricarboxylic acid cycle, caused by aconitase inhibition. Our results hence explain the slow growth of mitochondrial genome-deficient cells with a partial auxotrophy in four amino acids that results from distorted iron metabolism and an inhibited tricarboxylic acid cycle.
    DOI:  https://doi.org/10.1038/s42255-021-00477-6
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