bims-mitran 2022-01-23 papers

Issue of 2022–01–23
four papers selected by
Andreas Kohler, Stockholm University

Proc Natl Acad Sci U S A. 2022 Jan 18. pii: e2114710118. [Epub ahead of print]119(3):

Mitoribosomal small subunit maturation involves formation of initiation-like complexes.

Tea Lenarčič, Moritz Niemann, David J F Ramrath, Salvatore Calderaro, Timo Flügel, Martin Saurer, Marc Leibundgut, Daniel Boehringer, Céline Prange, Elke K Horn, André Schneider, Nenad Ban.

Mitochondrial ribosomes (mitoribosomes) play a central role in synthesizing mitochondrial inner membrane proteins responsible for oxidative phosphorylation. Although mitoribosomes from different organisms exhibit considerable structural variations, recent insights into mitoribosome assembly suggest that mitoribosome maturation follows common principles and involves a number of conserved assembly factors. To investigate the steps involved in the assembly of the mitoribosomal small subunit (mt-SSU) we determined the cryoelectron microscopy structures of middle and late assembly intermediates of the Trypanosoma brucei mitochondrial small subunit (mt-SSU) at 3.6- and 3.7-Å resolution, respectively. We identified five additional assembly factors that together with the mitochondrial initiation factor 2 (mt-IF-2) specifically interact with functionally important regions of the rRNA, including the decoding center, thereby preventing premature mRNA or large subunit binding. Structural comparison of assembly intermediates with mature mt-SSU combined with RNAi experiments suggests a noncanonical role of mt-IF-2 and a stepwise assembly process, where modular exchange of ribosomal proteins and assembly factors together with mt-IF-2 ensure proper 9S rRNA folding and protein maturation during the final steps of assembly.

Keywords: mitochondria; ribosome assembly; structural biology; translation

DOI: https://doi.org/10.1073/pnas.2114710118

Int J Mol Sci. 2022 Jan 16. pii: 952. [Epub ahead of print]23(2):

The Role of Mitochondrial DNA Mutations in Cardiovascular Diseases.

Siarhei A Dabravolski, Victoria A Khotina, Vasily N Sukhorukov, Vladislav A Kalmykov, Liudmila M Mikhaleva, Alexander N Orekhov.

Cardiovascular diseases (CVD) are one of the leading causes of morbidity and mortality worldwide. mtDNA (mitochondrial DNA) mutations are known to participate in the development and progression of some CVD. Moreover, specific types of mitochondria-mediated CVD have been discovered, such as MIEH (maternally inherited essential hypertension) and maternally inherited CHD (coronary heart disease). Maternally inherited mitochondrial CVD is caused by certain mutations in the mtDNA, which encode structural mitochondrial proteins and mitochondrial tRNA. In this review, we focus on recently identified mtDNA mutations associated with CVD (coronary artery disease and hypertension). Additionally, new data suggest the role of mtDNA mutations in Brugada syndrome and ischemic stroke, which before were considered only as a result of mutations in nuclear genes. Moreover, we discuss the molecular mechanisms of mtDNA involvement in the development of the disease.

Keywords: Brugada syndrome; atherosclerosis; cardiovascular diseases; coronary artery disease; hypertension; ischemic stroke; mitochondria

DOI: https://doi.org/10.3390/ijms23020952

Nat Commun. 2022 Jan 18. 13(1): 366

Nuclear and mitochondrial DNA editing in human cells with zinc finger deaminases.

Kayeong Lim, Sung-Ik Cho, Jin-Soo Kim.

Base editing in nuclear DNA and mitochondrial DNA (mtDNA) is broadly useful for biomedical research, medicine, and biotechnology. Here, we present a base editing platform, termed zinc finger deaminases (ZFDs), composed of custom-designed zinc-finger DNA-binding proteins, the split interbacterial toxin deaminase DddAtox, and a uracil glycosylase inhibitor (UGI), which catalyze targeted C-to-T base conversions without inducing unwanted small insertions and deletions (indels) in human cells. We assemble plasmids encoding ZFDs using publicly available zinc finger resources to achieve base editing at frequencies of up to 60% in nuclear DNA and 30% in mtDNA. Because ZFDs, unlike CRISPR-derived base editors, do not cleave DNA to yield single- or double-strand breaks, no unwanted indels caused by error-prone non-homologous end joining are produced at target sites. Furthermore, recombinant ZFD proteins, expressed in and purified from E. coli, penetrate cultured human cells spontaneously to induce targeted base conversions, demonstrating the proof-of-principle of gene-free gene therapy.

DOI: https://doi.org/10.1038/s41467-022-27962-0