bims-cytox1 2020-07-19 papers

Issue of 2020–07–19
six papers selected by
Gavin McStay, Staffordshire University

Mitochondrion. 2020 Jul 10. pii: S1567-7249(20)30151-3. [Epub ahead of print]

A novel m.11406T>A mutation in mitochondrial ND4 gene causes MELAS Syndrome.

Yan Lin, Xuebi Xu, Dandan Zhao, Fuchen Liu, Yuebei Luo, Jixiang Du, Dongdong Wang, Kunqian Ji, Yuying Zhao, Chuanzhu Yan.

Pathogenic point mutations of mitochondrial DNA (mtDNA) are associated with a large number of heterogeneous diseases involving multiple systems with which patients may present with a wide range of clinical phenotypes. In this study, we describe a novel heteroplasmic missense mutation, m.11406T>A, of the ND4 gene encoding the subunit 4 of mitochondrial complex I in a 32-year-old woman with recurrent epileptic seizure, headache and bilateral hearing loss. Skeletal muscle histochemistry demonstrated that approximately 20% of fibers were cytochrome C oxidase (COX) deficient with increased activity of succinate dehydrogenase (SDH). Further investigations in muscle specimens showed significantly reduced level of ND4 protein. It is interesting that the subunits of complex I (ND1 and NDFUB8) and complex IV(CO1) were also remarkably decreased. These findings indicate that ND1, NDFUB8 and CO1 are more susceptible than other subunits to mutations in the mitochondrial ND4 gene.

Keywords: MELAS syndrome; ND4 gene; complex I; mitochondrial DNA; mutation

DOI: https://doi.org/10.1016/j.mito.2020.06.011

Trends Genet. 2020 Jul 13. pii: S0168-9525(20)30155-4. [Epub ahead of print]

Mitochondrial Diseases: A Diagnostic Revolution.

Katherine R Schon, Thiloka Ratnaike, Jelle van den Ameele, Rita Horvath, Patrick F Chinnery.

Mitochondrial disorders have emerged as a common cause of inherited disease, but are traditionally viewed as being difficult to diagnose clinically, and even more difficult to comprehensively characterize at the molecular level. However, new sequencing approaches, particularly whole-genome sequencing (WGS), have dramatically changed the landscape. The combined analysis of nuclear and mitochondrial DNA (mtDNA) allows rapid diagnosis for the vast majority of patients, but new challenges have emerged. We review recent discoveries that will benefit patients and families, and highlight emerging questions that remain to be resolved.

Keywords: genetic diagnosis; mitochondrial disease; molecular diagnostics; mtDNA mutation; whole-genome sequencing

DOI: https://doi.org/10.1016/j.tig.2020.06.009

Mol Cell. 2020 Jul 11. pii: S1097-2765(20)30432-9. [Epub ahead of print]

Structural Insights into the Mechanism of Mitoribosomal Large Subunit Biogenesis.

Mateusz Jaskolowski, David J F Ramrath, Philipp Bieri, Moritz Niemann, Simone Mattei, Salvatore Calderaro, Marc Leibundgut, Elke K Horn, Daniel Boehringer, André Schneider, Nenad Ban.

In contrast to the bacterial translation machinery, mitoribosomes and mitochondrial translation factors are highly divergent in terms of composition and architecture. There is increasing evidence that the biogenesis of mitoribosomes is an intricate pathway, involving many assembly factors. To better understand this process, we investigated native assembly intermediates of the mitoribosomal large subunit from the human parasite Trypanosoma brucei using cryo-electron microscopy. We identify 28 assembly factors, 6 of which are homologous to bacterial and eukaryotic ribosome assembly factors. They interact with the partially folded rRNA by specifically recognizing functionally important regions such as the peptidyltransferase center. The architectural and compositional comparison of the assembly intermediates indicates a stepwise modular assembly process, during which the rRNA folds toward its mature state. During the process, several conserved GTPases and a helicase form highly intertwined interaction networks that stabilize distinct assembly intermediates. The presented structures provide general insights into mitoribosomal maturation.

Keywords: Trypanosoma brucei; assembly factors; cryo-EM structure; mitochondrial ribosome; mitoribosome; peptidyltransferase center; ribosomal GTPases; ribosomal maturation; ribosome assembly; ribosome biogenesis

DOI: https://doi.org/10.1016/j.molcel.2020.06.030

Elife. 2020 Jul 13. pii: e56649. [Epub ahead of print]9

Assigning mitochondrial localization of dual localized proteins using a yeast Bi-Genomic Mitochondrial-Split-GFP.

Gaétan Bader, Ludovic Enkler, Yuhei Araiso, Marine Hemmerle, Krystyna Binko, Emilia Baranowska, Johan-Owen De Craene, Julie Ruer-Laventie, Jean Pieters, Déborah Tribouillard-Tanvier, Bruno Senger, Jean-Paul di Rago, Sylvie Friant, Roza Kucharczyk, Hubert Dominique Becker.

A single nuclear gene can be translated into a dual localized protein that distributes between the cytosol and mitochondria. Accumulating evidences show that mitoproteomes contain lots of these dual localized proteins termed echoforms. Unraveling the existence of mitochondrial echoforms using current GFP (Green Fluorescent Protein) fusion microscopy approaches is extremely difficult because the GFP signal of the cytosolic echoform will almost inevitably mask that of the mitochondrial echoform. We therefore engineered a yeast strain expressing a new type of Split-GFP that we termed Bi-Genomic Mitochondrial-Split-GFP (BiG Mito-Split-GFP). Because one moiety of the GFP is translated from the mitochondrial machinery while the other is fused to the nuclear-encoded protein of interest translated in the cytosol, the self-reassembly of this Bi-Genomic-encoded Split-GFP is confined to mitochondria. We could authenticate the mitochondrial importability of any protein or echoform from yeast, but also from other organisms such as the human Argonaute 2 mitochondrial echoform.

Keywords: S. cerevisiae; Split-GFP; aminoacyl-tRNA synthetase; argonaute 2 protein; cell biology; dual localized protein; import; mitochondria

DOI: https://doi.org/10.7554/eLife.56649

Nature. 2020 Jul;583(7816): 332

Mitochondrial genome editing: another win for curiosity-driven research.

Keywords: Biological techniques; CRISPR-Cas9 genome editing; Genetics; Metabolism

DOI: https://doi.org/10.1038/d41586-020-02094-x