bims-cytox1 2019-12-22 papers

Issue of 2019–12–22
three papers selected by
Gavin McStay, Staffordshire University

Sci Adv. 2019 Dec;5(12): eaax9484

High-resolution cryo-EM structures of respiratory complex I: Mechanism, assembly, and disease.

Kristian Parey, Outi Haapanen, Vivek Sharma, Harald Köfeler, Thomas Züllig, Simone Prinz, Karin Siegmund, Ilka Wittig, Deryck J Mills, Janet Vonck, Werner Kühlbrandt, Volker Zickermann.

Respiratory complex I is a redox-driven proton pump, accounting for a large part of the electrochemical gradient that powers mitochondrial adenosine triphosphate synthesis. Complex I dysfunction is associated with severe human diseases. Assembly of the one-megadalton complex I in the inner mitochondrial membrane requires assembly factors and chaperones. We have determined the structure of complex I from the aerobic yeast Yarrowia lipolytica by electron cryo-microscopy at 3.2-Å resolution. A ubiquinone molecule was identified in the access path to the active site. The electron cryo-microscopy structure indicated an unusual lipid-protein arrangement at the junction of membrane and matrix arms that was confirmed by molecular simulations. The structure of a complex I mutant and an assembly intermediate provide detailed molecular insights into the cause of a hereditary complex I-linked disease and complex I assembly in the inner mitochondrial membrane.

DOI: https://doi.org/10.1126/sciadv.aax9484

Cells. 2019 Dec 19. pii: E17. [Epub ahead of print]9(1):

Mitochondrial Gene Expression and Beyond-Novel Aspects of Cellular Physiology.

Anna V Kotrys, Roman J Szczesny.

Mitochondria are peculiar organelles whose proper function depends on the crosstalk between two genomes, mitochondrial and nuclear. The human mitochondrial genome (mtDNA) encodes only 13 proteins; nevertheless, its proper expression is essential for cellular homeostasis, as mtDNA-encoded proteins are constituents of mitochondrial respiratory complexes. In addition, mtDNA expression results in the production of RNA molecules, which influence cell physiology once released from the mitochondria into the cytoplasm. As a result, dysfunctions of mtDNA expression may lead to pathologies in humans. Here, we review the mechanisms of mitochondrial gene expression with a focus on recent findings in the field. We summarize the complex turnover of mitochondrial transcripts and present an increasing body of evidence indicating new functions of mitochondrial transcripts. We discuss mitochondrial gene regulation in different cellular contexts, focusing on stress conditions. Finally, we highlight the importance of emerging aspects of mitochondrial gene regulation in human health and disease.

Keywords: dsRNA; innate immunity; interferon response; mitochondria; mitochondrial gene expression; mtDNA; mtDNA transcription; mtRNA; post-transcriptional mtRNA processing

DOI: https://doi.org/10.3390/cells9010017

Cell Rep. 2019 Dec 17. pii: S2211-1247(19)31537-2. [Epub ahead of print]29(12): 3825-3834.e4

Proteomics of Cytochrome c Oxidase-Negative versus -Positive Muscle Fiber Sections in Mitochondrial Myopathy.

Marta Murgia, Jing Tan, Philipp E Geyer, Sophia Doll, Matthias Mann, Thomas Klopstock.

The mosaic distribution of cytochrome c oxidase+ (COX+) and COX- muscle fibers in mitochondrial disorders allows the sampling of fibers with compensated and decompensated mitochondrial function from the same individual. We apply laser capture microdissection to excise individual COX+ and COX- fibers from the biopsies of mitochondrial myopathy patients. Using mass spectrometry-based proteomics, we quantify >4,000 proteins per patient. While COX+ fibers show a higher expression of respiratory chain components, COX- fibers display protean adaptive responses, including upregulation of mitochondrial ribosomes, translation proteins, and chaperones. Upregulated proteins include C1QBP, required for mitoribosome formation and protein synthesis, and STOML2, which organizes cardiolipin-enriched microdomains and the assembly of respiratory supercomplexes. Factoring in fast/slow fiber type, COX- slow fibers show a compensatory upregulation of beta-oxidation, the AAA+ protease AFG3L1, and the OPA1-dependent cristae remodeling program. These findings reveal compensatory mechanisms in muscle fibers struggling with energy shortage and metabolic stress.

Keywords: COX; CPEO; chronic progressive external ophthalmoplegia; cytochrome c oxidase; laser microdissection; mass spectrometry; mitochondrial myopathy; proteomics; single muscle fibers

DOI: https://doi.org/10.1016/j.celrep.2019.11.055