bims-tricox 2023-02-12 papers

bims-tricox

Biomed News

on Translation, ribosomes and COX

Issue of 2023–02–12
six papers selected by
Yash Verma, University of Delhi South Campus

Ribosome biogenesis factors-from names to functions.
The Journey of Mitochondrial Protein Import and the Roadmap to Follow.
Do mitochondria use efflux pumps to protect their ribosomes from antibiotics?
Yet Another Similarity between Mitochondrial and Bacterial Ribosomal Small Subunit Biogenesis Obtained by Structural Characterization of RbfA from S. aureus.
How hot can mitochondria be? Incubation at temperatures above 43 °C induces the degradation of respiratory complexes and supercomplexes in intact cells and isolated mitochondria.
Mitochondrial Transplantation in Mitochondrial Medicine: Current Challenges and Future Perspectives.

EMBO J. 2023 Feb 10. e112699

Ribosome biogenesis factors-from names to functions.

Kerstin Dörner, Chiara Ruggeri, Ivo Zemp, Ulrike Kutay.

  The assembly of ribosomal subunits is a highly orchestrated process that involves a huge cohort of accessory factors. Most eukaryotic ribosome biogenesis factors were first identified by genetic screens and proteomic approaches of pre-ribosomal particles in Saccharomyces cerevisiae. Later, research on human ribosome synthesis not only demonstrated that the requirement for many of these factors is conserved in evolution, but also revealed the involvement of additional players, reflecting a more complex assembly pathway in mammalian cells. Yet, it remained a challenge for the field to assign a function to many of the identified factors and to reveal their molecular mode of action. Over the past decade, structural, biochemical, and cellular studies have largely filled this gap in knowledge and led to a detailed understanding of the molecular role that many of the players have during the stepwise process of ribosome maturation. Such detailed knowledge of the function of ribosome biogenesis factors will be key to further understand and better treat diseases linked to disturbed ribosome assembly, including ribosomopathies, as well as different types of cancer.

Keywords:  pre-rRNA processing; pre-ribosomal particle; ribosomal subunit; ribosome biogenesis factor; ribosome synthesis

DOI:  https://doi.org/10.15252/embj.2022112699
Int J Mol Sci. 2023 Jan 27. pii: 2479. [Epub ahead of print]24(3):

The Journey of Mitochondrial Protein Import and the Roadmap to Follow.

Mary Oluwadamilola Haastrup, Kunwar Somesh Vikramdeo, Seema Singh, Ajay Pratap Singh, Santanu Dasgupta.

  Mitochondria are double membrane-bound organelles that play critical functions in cells including metabolism, energy production, regulation of intrinsic apoptosis, and maintenance of calcium homeostasis. Mitochondria are fascinatingly equipped with their own genome and machinery for transcribing and translating 13 essential proteins of the oxidative phosphorylation system (OXPHOS). The rest of the proteins (99%) that function in mitochondria in the various pathways described above are nuclear-transcribed and synthesized as precursors in the cytosol. These proteins are imported into the mitochondria by the unique mitochondrial protein import system that consists of seven machineries. Proper functioning of the mitochondrial protein import system is crucial for optimal mitochondrial deliverables, as well as mitochondrial and cellular homeostasis. Impaired mitochondrial protein import leads to proteotoxic stress in both mitochondria and cytosol, inducing mitochondrial unfolded protein response (UPRmt). Altered UPRmt is associated with the development of various disease conditions including neurodegenerative and cardiovascular diseases, as well as cancer. This review sheds light on the molecular mechanisms underlying the import of nuclear-encoded mitochondrial proteins, the consequences of defective mitochondrial protein import, and the pathological conditions that arise due to altered UPRmt.

Keywords:  diseases; mitochondria; mitochondrial protein import machineries; mitochondrial unfolded protein response; proteins

DOI:  https://doi.org/10.3390/ijms24032479
Microbiology (Reading). 2023 Jan;169(1):

Do mitochondria use efflux pumps to protect their ribosomes from antibiotics?

Md Deen Islam, Brian D Harrison, Judy J-Y Li, Austein G McLoughlin, Deborah A Court.

  Fungal environments are rich in natural and engineered antimicrobials, and this, combined with the fact that fungal genomes are rich in coding sequences for transporters, suggests that fungi are an intriguing group in which to search for evidence of antimicrobial efflux pumps in mitochondria. Herein, the range of protective mechanisms used by fungi against antimicrobials is introduced, and it is hypothesized, based on the susceptibility of mitochondrial and bacterial ribosomes to the same antibiotics, that mitochondria might also contain pumps that efflux antibiotics from these organelles. Preliminary evidence of ethidium bromide efflux is presented and several candidate efflux pumps are identified in fungal mitochondrial proteomes.

Keywords:  ABC transporters; MFS transporters; Neurospora crassa; Saccharomyces cerevisiae; mitochondria drug efflux; mitochondrial ribosomes

DOI:  https://doi.org/10.1099/mic.0.001272
Int J Mol Sci. 2023 Jan 20. pii: 2118. [Epub ahead of print]24(3):

Yet Another Similarity between Mitochondrial and Bacterial Ribosomal Small Subunit Biogenesis Obtained by Structural Characterization of RbfA from S. aureus.

Aydar G Bikmullin, Bulat Fatkhullin, Artem Stetsenko, Azat Gabdulkhakov, Natalia Garaeva, Liliia Nurullina, Evelina Klochkova, Alexander Golubev, Iskander Khusainov, Natalie Trachtmann, Dmitriy Blokhin, Albert Guskov, Shamil Validov, Konstantin Usachev, Marat Yusupov.

  Ribosome biogenesis is a complex and highly accurate conservative process of ribosomal subunit maturation followed by association. Subunit maturation comprises sequential stages of ribosomal RNA and proteins' folding, modification and binding, with the involvement of numerous RNAses, helicases, GTPases, chaperones, RNA, protein-modifying enzymes, and assembly factors. One such assembly factor involved in bacterial 30S subunit maturation is ribosomal binding factor A (RbfA). In this study, we present the crystal (determined at 2.2 Å resolution) and NMR structures of RbfA as well as the 2.9 Å resolution cryo-EM reconstruction of the 30S-RbfA complex from Staphylococcus aureus (S. aureus). Additionally, we show that the manner of RbfA action on the small ribosomal subunit during its maturation is shared between bacteria and mitochondria. The obtained results clarify the function of RbfA in the 30S maturation process and its role in ribosome functioning in general. Furthermore, given that S. aureus is a serious human pathogen, this study provides an additional prospect to develop antimicrobials targeting bacterial pathogens.

Keywords:  30S biogenesis; RbfA; Staphylococcus aureus; bacterial ribosomal proteins; ribosome; translation

DOI:  https://doi.org/10.3390/ijms24032118
Mitochondrion. 2023 Feb 08. pii: S1567-7249(23)00011-9. [Epub ahead of print]

How hot can mitochondria be? Incubation at temperatures above 43 °C induces the degradation of respiratory complexes and supercomplexes in intact cells and isolated mitochondria.

Raquel Moreno-Loshuertos, Joaquín Marco-Brualla, Patricia Meade, Ruth Soler-Agesta, José A Enriquez, Patricio Fernández-Silva.

  Mitochondrial function generates an important fraction of the heat that contributes to cellular and organismal temperature maintenance, but the actual values of this parameter reached in the organelles is a matter of debate. The studies addressing this issue have reported divergent results: from detecting in the organelles the same temperature as the cell average or the incubation temperature, to increasing differences of up to 10 degrees above the incubation value. Theoretical calculations based on physical laws exclude the possibility of relevant temperature gradients between mitochondria and their surroundings. These facts have given rise to a conundrum or paradox about hot mitochondria. We have examined by Blue-Native electrophoresis, both in intact cells and in isolated organelles, the stability of respiratory complexes and supercomplexes at different temperatures to obtain information about their tolerance to heat stress. We observe that, upon incubation at values above 43 °C and after relatively short periods, respiratory complexes, and especially complex I and its supercomplexes, are unstable even when the respiratory activity is inhibited. These results support the conclusion that high temperatures (> 43 °C) cause damage to mitochondrial structure and function and question the proposal that these organelles can physiologically work at close to 50 °C.

Keywords:  hyperthermia; mitochondria; respiratory complex; stability; supercomplex; temperature

DOI:  https://doi.org/10.1016/j.mito.2023.02.002
Int J Mol Sci. 2023 Jan 19. pii: 1969. [Epub ahead of print]24(3):

Mitochondrial Transplantation in Mitochondrial Medicine: Current Challenges and Future Perspectives.

Marco D'Amato, Francesca Morra, Ivano Di Meo, Valeria Tiranti.

  Mitochondrial diseases (MDs) are inherited genetic conditions characterized by pathogenic mutations in nuclear DNA (nDNA) or mitochondrial DNA (mtDNA). Current therapies are still far from being fully effective and from covering the broad spectrum of mutations in mtDNA. For example, unlike heteroplasmic conditions, MDs caused by homoplasmic mtDNA mutations do not yet benefit from advances in molecular approaches. An attractive method of providing dysfunctional cells and/or tissues with healthy mitochondria is mitochondrial transplantation. In this review, we discuss what is known about intercellular transfer of mitochondria and the methods used to transfer mitochondria both in vitro and in vivo, and we provide an outlook on future therapeutic applications. Overall, the transfer of healthy mitochondria containing wild-type mtDNA copies could induce a heteroplasmic shift even when homoplasmic mtDNA variants are present, with the aim of attenuating or preventing the progression of pathological clinical phenotypes. In summary, mitochondrial transplantation is a challenging but potentially ground-breaking option for the treatment of various mitochondrial pathologies, although several questions remain to be addressed before its application in mitochondrial medicine.

Keywords:  mitochondria; mitochondrial diseases; mitochondrial dysfunction; mitochondrial medicine; mitochondrial transplantation

DOI:  https://doi.org/10.3390/ijms24031969