bims-cytox1 2021-02-07 papers

Issue of 2021–02–07
four papers selected by
Gavin McStay, Staffordshire University

Proc Natl Acad Sci U S A. 2021 Feb 09. pii: e2008778118. [Epub ahead of print]118(6):

High-resolution imaging reveals compartmentalization of mitochondrial protein synthesis in cultured human cells.

Matthew Zorkau, Christin A Albus, Rolando Berlinguer-Palmini, Zofia M A Chrzanowska-Lightowlers, Robert N Lightowlers.

Human mitochondria contain their own genome, mitochondrial DNA, that is expressed in the mitochondrial matrix. This genome encodes 13 vital polypeptides that are components of the multisubunit complexes that couple oxidative phosphorylation (OXPHOS). The inner mitochondrial membrane that houses these complexes comprises the inner boundary membrane that runs parallel to the outer membrane, infoldings that form the cristae membranes, and the cristae junctions that separate the two. It is in these cristae membranes that the OXPHOS complexes have been shown to reside in various species. The majority of the OXPHOS subunits are nuclear-encoded and must therefore be imported from the cytosol through the outer membrane at contact sites with the inner boundary membrane. As the mitochondrially encoded components are also integral members of these complexes, where does protein synthesis occur? As transcription, mRNA processing, maturation, and at least part of the mitoribosome assembly process occur at the nucleoid and the spatially juxtaposed mitochondrial RNA granules, is protein synthesis also performed at the RNA granules close to these entities, or does it occur distal to these sites? We have adapted a click chemistry-based method coupled with stimulated emission depletion nanoscopy to address these questions. We report that, in human cells in culture, within the limits of our methodology, the majority of mitochondrial protein synthesis is detected at the cristae membranes and is spatially separated from the sites of RNA processing and maturation.

Keywords: click chemistry; human mitochondria; mitoribosomes; protein synthesis

DOI: https://doi.org/10.1073/pnas.2008778118

Proc Natl Acad Sci U S A. 2021 Feb 09. pii: e2017774118. [Epub ahead of print]118(6):

Determinism and contingencies shaped the evolution of mitochondrial protein import.

Samuel Rout, Silke Oeljeklaus, Abhijith Makki, Jan Tachezy, Bettina Warscheid, André Schneider.

Mitochondrial protein import requires outer membrane receptors that evolved independently in different lineages. Here we used quantitative proteomics and in vitro binding assays to investigate the substrate preferences of ATOM46 and ATOM69, the two mitochondrial import receptors of Trypanosoma brucei The results show that ATOM46 prefers presequence-containing, hydrophilic proteins that lack transmembrane domains (TMDs), whereas ATOM69 prefers presequence-lacking, hydrophobic substrates that have TMDs. Thus, the ATOM46/yeast Tom20 and the ATOM69/yeast Tom70 pairs have similar substrate preferences. However, ATOM46 mainly uses electrostatic, and Tom20 hydrophobic, interactions for substrate binding. In vivo replacement of T. brucei ATOM46 by yeast Tom20 did not restore import. However, replacement of ATOM69 by the recently discovered Tom36 receptor of Trichomonas hydrogenosomes, while not allowing for growth, restored import of a large subset of trypanosomal proteins that lack TMDs. Thus, even though ATOM69 and Tom36 share the same domain structure and topology, they have different substrate preferences. The study establishes complementation experiments, combined with quantitative proteomics, as a highly versatile and sensitive method to compare in vivo preferences of protein import receptors. Moreover, it illustrates the role determinism and contingencies played in the evolution of mitochondrial protein import receptors.

Keywords: Trichomonas; Trypanosoma; mitochondria; protein import; receptors

DOI: https://doi.org/10.1073/pnas.2017774118

Int J Mol Sci. 2021 Feb 02. pii: 1462. [Epub ahead of print]22(3):

Ordered Clusters of the Complete Oxidative Phosphorylation System in Cardiac Mitochondria.

Semen Nesterov, Yury Chesnokov, Roman Kamyshinsky, Alisa Panteleeva, Konstantin Lyamzaev, Raif Vasilov, Lev Yaguzhinsky.

The existence of a complete oxidative phosphorylation system (OXPHOS) supercomplex including both electron transport system and ATP synthases has long been assumed based on functional evidence. However, no structural confirmation of the docking between ATP synthase and proton pumps has been obtained. In this study, cryo-electron tomography was used to reveal the supramolecular architecture of the rat heart mitochondria cristae during ATP synthesis. Respirasome and ATP synthase structure in situ were determined using subtomogram averaging. The obtained reconstructions of the inner mitochondrial membrane demonstrated that rows of respiratory chain supercomplexes can dock with rows of ATP synthases forming oligomeric ordered clusters. These ordered clusters indicate a new type of OXPHOS structural organization. It should ensure the quickness, efficiency, and damage resistance of OXPHOS, providing a direct proton transfer from pumps to ATP synthase along the lateral pH gradient without energy dissipation.

Keywords: ATP synthase; cryo-electron microscopy; mitochondria; oxidative phosphorylation; respirasome; supercomplex

DOI: https://doi.org/10.3390/ijms22031462

CNS Neurosci Ther. 2021 Feb 03.

Stem cell-derived mitochondria transplantation: A promising therapy for mitochondrial encephalomyopathy.

Kaiming Liu, Zhijian Zhou, Mengxiong Pan, Lining Zhang.

Mitochondrial encephalomyopathies are disorders caused by mitochondrial and nuclear DNA mutations which affect the nervous and muscular systems. Current therapies for mitochondrial encephalomyopathies are inadequate and mostly palliative. However, stem cell-derived mitochondria transplantation has been demonstrated to play an key part in metabolic rescue, which offers great promise for mitochondrial encephalomyopathies. Here, we summarize the present status of stem cell therapy for mitochondrial encephalomyopathy and discuss mitochondrial transfer routes and the protection mechanisms of stem cells. We also identify and summarize future perspectives and challenges for the treatment of these intractable disorders based on the concept of mitochondrial transfer from stem cells.

Keywords: mitochondria; mitochondria quality control; mitochondrial dynamics; mitochondrial encephalomyopathy; stem cell; tunneling nanotube

DOI: https://doi.org/10.1111/cns.13618