bims-cytox1 Biomed News
on Cytochrome oxidase subunit 1
Issue of 2020‒08‒23
seven papers selected by
Gavin McStay
Staffordshire University


  1. Int J Mol Sci. 2020 Aug 16. pii: E5880. [Epub ahead of print]21(16):
    Yamada M, Akashi K, Ooka R, Miyado K, Akutsu H.
      Mitochondria are energy-producing intracellular organelles containing their own genetic material in the form of mitochondrial DNA (mtDNA), which codes for proteins and RNAs essential for mitochondrial function. Some mtDNA mutations can cause mitochondria-related diseases. Mitochondrial diseases are a heterogeneous group of inherited disorders with no cure, in which mutated mtDNA is passed from mothers to offspring via maternal egg cytoplasm. Mitochondrial replacement (MR) is a genome transfer technology in which mtDNA carrying disease-related mutations is replaced by presumably disease-free mtDNA. This therapy aims at preventing the transmission of known disease-causing mitochondria to the next generation. Here, a proof of concept for the specific removal or editing of mtDNA disease-related mutations by genome editing is introduced. Although the amount of mtDNA carryover introduced into human oocytes during nuclear transfer is low, the safety of mtDNA heteroplasmy remains a concern. This is particularly true regarding donor-recipient mtDNA mismatch (mtDNA-mtDNA), mtDNA-nuclear DNA (nDNA) mismatch caused by mixing recipient nDNA with donor mtDNA, and mtDNA replicative segregation. These conditions can lead to mtDNA genetic drift and reversion to the original genotype. In this review, we address the current state of knowledge regarding nuclear transplantation for preventing the inheritance of mitochondrial diseases.
    Keywords:  Mitochondria DNA (mtDNA), nuclear transfer; maternal inheritance; mitochondria replacement (MR), nDNA–mtDNA compatibility; mitochondrial function; mtDNA genetic drift; mtDNA heteroplasmy; mtDNA replicative segregation; mtDNA–mtDNA compatibility
    DOI:  https://doi.org/10.3390/ijms21165880
  2. Elife. 2020 08 19. pii: e58362. [Epub ahead of print]9
    Aibara S, Singh V, Modelska A, Amunts A.
      Translation of mitochondrial messenger RNA (mt-mRNA) is performed by distinct mitoribosomes comprising at least 36 mitochondria-specific proteins. How these mitoribosomal proteins assist in the binding of mt-mRNA and to what extent they are involved in the translocation of transfer RNA (mt-tRNA) is unclear. To visualize the process of translation in human mitochondria, we report ~3.0 Å resolution structure of the human mitoribosome, including the L7/L12 stalk, and eight structures of its functional complexes with mt-mRNA, mt-tRNAs, recycling factor and additional trans factors. The study reveals a transacting protein module LRPPRC-SLIRP that delivers mt-mRNA to the mitoribosomal small subunit through a dedicated platform formed by the mitochondria-specific protein mS39. Mitoribosomal proteins of the large subunit mL40, mL48, and mL64 coordinate translocation of mt-tRNA. The comparison between those structures shows dynamic interactions between the mitoribosome and its ligands, suggesting a sequential mechanism of conformational changes.
    Keywords:  RNA; cryo-EM; gene expression; human; mitochondria; molecular biophysics; ribosome; structural biology; translation
    DOI:  https://doi.org/10.7554/eLife.58362
  3. J Biol Chem. 2020 Aug 21. pii: jbc.RA120.014247. [Epub ahead of print]
    Zöller E, Laborenz J, Krämer L, Boos F, Räschle M, Alexander RT, Herrmann JM.
      The biogenesis of mitochondria requires the import of hundreds of precursor proteins. These proteins are transported post-translationally with the help of chaperones, meaning that the overproduction of mitochondrial proteins or the limited availability of chaperones can lead to the accumulation of cytosolic precursor proteins. This imposes a severe challenge to cytosolic proteostasis, and triggers a specific transcription program, called the mitoprotein-induced stress response, which activates the proteasome system. This coincides with the repression of mitochondrial proteins, including many proteins of the intermembrane space (IMS). In contrast, herein we report that the so far uncharacterized IMS protein Mix23 is considerably up-regulated when mitochondrial import is perturbed. Mix23 is evolutionarily conserved and a homolog of the human coiled-coil domain containing 58, CCDC58. We found that, like the subunits of the proteasome, Mix23 is under control of the transcription factor Rpn4. It is imported into mitochondria by the mitochondrial disulfide relay. Mix23 is critical for the efficient import of proteins into the mitochondrial matrix particularly if the function of the TIM23 translocase is compromised such as in temperature-sensitive mutants of Tim17. Our observations identify Mix23 as a novel regulator or stabilizer of the mitochondrial protein import machinery that is specifically upregulated upon mitoprotein-induced stress conditions.
    Keywords:  Intermembrane space; disulfide; mitochondria; proteasome; protein translocation; proteostasis; stress response
    DOI:  https://doi.org/10.1074/jbc.RA120.014247
  4. J Biochem. 2020 Aug 20. pii: mvaa098. [Epub ahead of print]
    Kazuhito T, Wei FY.
      A fundamental aspect of mitochondria is that they possess DNA and protein translation machinery. Mitochondrial DNA encodes 22 tRNAs that translate mitochondrial mRNAs to 13 polypeptides of respiratory complexes. Various chemical modifications have been identified in mitochondrial tRNAs via complex enzymatic processes. A growing body of evidence has demonstrated that these modifications are essential for translation by regulating tRNA stability, structure, and mRNA binding, and can be dynamically regulated by the metabolic environment. Importantly, the hypomodification of mitochondrial tRNA due to pathogenic mutations in mitochondrial tRNA genes or nuclear genes encoding modifying enzymes can result in life-threatening mitochondrial diseases in humans. Thus, the mitochondrial tRNA modification is a fundamental mechanism underlying the tight regulation of mitochondrial translation and is essential for life. In this review, we focus on recent findings on the physiological roles of 5-taurinomethyl modification (herein referred as taurine modification) in mitochondrial tRNAs. We summarize the findings in human patients and animal models with a deficiency of taurine modifications and provide pathogenic links to mitochondrial diseases. We anticipate that this review will help understand the complexity of mitochondrial biology and disease.
    DOI:  https://doi.org/10.1093/jb/mvaa098
  5. Sci Adv. 2020 Aug;6(32): eabc7288
    Ruan L, McNamara JT, Zhang X, Chang AC, Zhu J, Dong Y, Sun G, Peterson A, Na CH, Li R.
      Proteostasis declines with age, characterized by the accumulation of unfolded or damaged proteins. Recent studies suggest that proteins constituting pathological inclusions in neurodegenerative diseases also enter and accumulate in mitochondria. How unfolded proteins are managed within mitochondria remains unclear. Here, we found that excessive unfolded proteins in the mitochondrial matrix of yeast cells are consolidated into solid-phase inclusions, which we term deposits of unfolded mitochondrial proteins (DUMP). Formation of DUMP occurs in mitochondria near endoplasmic reticulum-mitochondria contact sites and is regulated by mitochondrial proteins controlling the production of cytidine 5'-diphosphate-diacylglycerol. DUMP formation is age dependent but accelerated by exogenous unfolded proteins. Many enzymes of the tricarboxylic acid cycle were enriched in DUMP. During yeast cell division, DUMP formation is necessary for asymmetric inheritance of damaged mitochondrial proteins between mother and daughter cells. We provide evidence that DUMP-like structures may be induced by excessive unfolded proteins in human cells.
    DOI:  https://doi.org/10.1126/sciadv.abc7288
  6. Trends Genet. 2020 Aug 17. pii: S0168-9525(20)30201-8. [Epub ahead of print]
    Riepsaame J.
      Precise gene editing of mitochondrial DNA (mtDNA) is essential for the generation of model systems to study rare mitochondrial diseases but was long deemed impossible - until now. A recent publication by Mok et al. describes a gene editing tool capable of installing point mutations in mtDNA, and it does not involve CRISPR.
    DOI:  https://doi.org/10.1016/j.tig.2020.08.001
  7. Cell Res. 2020 Aug 17.
    Gao K, Cheng M, Zuo X, Lin J, Hoogewijs K, Murphy MP, Fu XD, Zhang X.
      RNA interference (RNAi) has been thought to be a gene-silencing pathway present in most eukaryotic cells to safeguard the genome against retrotransposition. Small interfering RNAs (siRNAs) have also become a powerful tool for studying gene functions. Given the endosymbiotic hypothesis that mitochondria originated from prokaryotes, mitochondria have been generally assumed to lack active RNAi; however, certain bacteria have Argonaute homologs and various reports suggest the presence of specific microRNAs and nuclear genome (nDNA)-encoded Ago2 in the mitochondria. Here we report that transfected siRNAs are not only able to enter the matrix of mitochondria, but also function there to specifically silence targeted mitochondrial transcripts. The mitoRNAi effect is readily detectable at the mRNA level, but only recordable on relatively unstable proteins, such as the mtDNA-encoded complex IV subunits. We also apply mitoRNAi to directly determine the postulated crosstalk between individual respiratory chain complexes, and our result suggests that the controversial observations previously made in patient-derived cells might result from differential adaptation in different cell lines. Our findings bring a new tool to study mitochondrial biology.
    DOI:  https://doi.org/10.1038/s41422-020-00394-5