bims-cytox1 2020-07-05 papers

Issue of 2020–07–05
four papers selected by
Gavin McStay, Staffordshire University

EMBO J. 2020 Jun 30. e104820

Structural insights into mammalian mitochondrial translation elongation catalyzed by mtEFG1.

Mitochondria are eukaryotic organelles of bacterial origin where respiration takes place to produce cellular chemical energy. These reactions are catalyzed by the respiratory chain complexes located in the inner mitochondrial membrane. Notably, key components of the respiratory chain complexes are encoded on the mitochondrial chromosome and their expression relies on a dedicated mitochondrial translation machinery. Defects in the mitochondrial gene expression machinery lead to a variety of diseases in humans mostly affecting tissues with high energy demand such as the nervous system, the heart, or the muscles. The mitochondrial translation system has substantially diverged from its bacterial ancestor, including alterations in the mitoribosomal architecture, multiple changes to the set of translation factors and striking reductions in otherwise conserved tRNA elements. Although a number of structures of mitochondrial ribosomes from different species have been determined, our mechanistic understanding of the mitochondrial translation cycle remains largely unexplored. Here, we present two cryo-EM reconstructions of human mitochondrial elongation factor G1 bound to the mammalian mitochondrial ribosome at two different steps of the tRNA translocation reaction during translation elongation. Our structures explain the mechanism of tRNA and mRNA translocation on the mitoribosome, the regulation of mtEFG1 activity by the ribosomal GTPase-associated center, and the basis of decreased susceptibility of mtEFG1 to the commonly used antibiotic fusidic acid.

Keywords: cryo-EM; elongation; mitoribosome; mtEFG1; translation

DOI: https://doi.org/10.15252/embj.2020104820

Sci Rep. 2020 Jul 02. 10(1): 10821

High throughput single cell analysis of mitochondrial heteroplasmy in mitochondrial diseases.

Ryotaro Maeda, Daisuke Kami, Hideki Maeda, Akira Shikuma, Satoshi Gojo.

Mitochondrial heteroplasmy, which fundamentally means intracellular heterogeneity of mitochondrial DNA (mtDNA), has been measured in a group of cells, regardless of intercellular heterogeneity. Ordinal methods for mitochondrial heteroplasmy cannot discriminate between an intercellular homogenic population composed of cells with similar intracellular heterogeneity for mtDNA and an intercellular heterogenic population composed of cells with different rates of mutated mtDNA. A high-throughput method to determine mitochondrial heteroplasmy in a single cell was developed by using droplet digital PCR with TaqMan polymerase in this study. This technique revealed that there are three different cell populations of cultured fibroblasts derived from patients with mitochondrial disease carrying a mutation in the mtDNA; cells with homoplasmy of either mutated or healthy mtDNA; and cells mixed with mutated and healthy mtDNA. The presence of intercellular heterogeneity, even in uniformed cultured fibroblasts, suggests that heterogeneity should exist among different kinds of cells. The diagnosis of intercellular heterogeneity with respect to mitochondrial heteroplasmy by this methodology could provide novel insight into developing a treatment strategy for mitochondrial diseases.

DOI: https://doi.org/10.1038/s41598-020-67686-z

Sci Rep. 2020 Jun 29. 10(1): 10304

Protonic Capacitor: Elucidating the biological significance of mitochondrial cristae formation.

James Weifu Lee.

For decades, it was not entirely clear why mitochondria develop cristae? The work employing the transmembrane-electrostatic proton localization theory reported here has now provided a clear answer to this fundamental question. Surprisingly, the transmembrane-electrostatically localized proton concentration at a curved mitochondrial crista tip can be significantly higher than that at the relatively flat membrane plane regions where the proton-pumping respiratory supercomplexes are situated. The biological significance for mitochondrial cristae has now, for the first time, been elucidated at a protonic bioenergetics level: 1) The formation of cristae creates more mitochondrial inner membrane surface area and thus more protonic capacitance for transmembrane-electrostatically localized proton energy storage; and 2) The geometric effect of a mitochondrial crista enhances the transmembrane-electrostatically localized proton density to the crista tip where the ATP synthase can readily utilize the localized proton density to drive ATP synthesis.

DOI: https://doi.org/10.1038/s41598-020-66203-6

J Inherit Metab Dis. 2020 Jul 03.

Moving Towards Clinical Trials for Mitochondrial Diseases.

Robert D S Pitceathly, Nandaki Keshavan, Joyeeta Rahman, Shamima Rahman.

Primary mitochondrial diseases represent some of the most common and severe inherited metabolic disorders, affecting approximately 1 in 4300 live births. The clinical and molecular diversity typified by mitochondrial diseases has contributed to the lack of licensed disease-modifying therapies available. Management for the majority of patients is primarily supportive. The failure of clinical trials in mitochondrial disease partly relates to the inefficacy of compounds studied. However, it is also likely to be a consequence of the significant challenges faced by clinicians and researchers when designing trials for mitochondrial diseases, which have historically been hampered by a lack of natural history data, biomarkers and outcome measures to detect a treatment effect. Encouragingly, over the past decade there have been significant advances in therapy development for mitochondrial diseases, with many small molecules now transitioning from preclinical to early phase human interventional studies. In this review, we present the treatments and management strategies currently available to people with mitochondrial disease. We evaluate the challenges and potential solutions to trial design and highlight the emerging pharmacological and genetic strategies that are moving from the laboratory to clinical trials for this group of disorders. This article is protected by copyright. All rights reserved.

Keywords: Primary mitochondrial disease; antioxidants; clinical trial; gene therapy; mitochondrial biogenesis; mitophagy; nucleosides; treatment

DOI: https://doi.org/10.1002/jimd.12281