bims-mitran 2022-01-02 papers

Issue of 2022–01–02
three papers selected by
Andreas Kohler, Stockholm University

Elife. 2021 Dec 31. pii: e68213. [Epub ahead of print]10

Defining the interactome of the human mitochondrial ribosome identifies SMIM4 and TMEM223 as respiratory chain assembly factors.

Sven Dennerlein, Sabine Poerschke, Silke Oeljeklaus, Cong Wang, Ricarda Richter-Dennerlein, Johannes Sattmann, Diana Bauermeister, Elisa Hanitsch, Stefan Stoldt, Thomas Langer, Stefan Jakobs, Bettina Warscheid, Peter Rehling.

Human mitochondria express a genome that encodes thirteen core subunits of the oxidative phosphorylation system (OXPHOS). These proteins insert into the inner membrane co-translationally. Therefore, mitochondrial ribosomes engage with the OXA1L-insertase and membrane-associated proteins, which support membrane insertion of translation products and early assembly steps into OXPHOS complexes. To identify ribosome-associated biogenesis factors for the OXPHOS system, we purified ribosomes and associated proteins from mitochondria. We identified TMEM223 as a ribosome-associated protein involved in complex IV biogenesis. TMEM223 stimulates the translation of COX1 mRNA and is a constituent of early COX1 assembly intermediates. Moreover, we show that SMIM4 together with C12ORF73 interacts with newly synthesized cytochrome b to support initial steps of complex III biogenesis in complex with UQCC1 and UQCC2. Our analyses define the interactome of the human mitochondrial ribosome and reveal novel assembly factors for complex III and IV biogenesis that link early assembly stages to the translation machinery.

Keywords: assembly; biochemistry; cell biology; chemical biology; mitochondria; oxidative phosphorylation; ribosome; translation

DOI: https://doi.org/10.7554/eLife.68213

J Biol Chem. 2021 Dec 22. pii: S0021-9258(21)01333-8. [Epub ahead of print] 101523

Oxidative stress induces Z-DNA binding protein 1-dependent activation of microglia via mtDNA released from retinal pigment epithelial cells.

Jamal Saada, Ryan J McAuley, Michela Marcatti, Tony Zifeng Tang, Massoud Motamedi, Bartosz Szczesny.

Oxidative stress, inflammation, and aberrant activation of microglia in the retina are commonly observed in ocular pathologies. In glaucoma or age-related macular degeneration, the chronic activation of microglia affects retinal ganglion cells and photoreceptors, respectively, contributing to gradual vision loss. However, the molecular mechanisms that cause activation of microglia in the retina are not fully understood. Here we show that exposure of retinal pigment epithelial (RPE) cells to chronic low-level oxidative stress induces mitochondrial DNA (mtDNA)-specific damage, and the subsequent translocation of damaged mtDNA to the cytoplasm results in the binding and activation of intracellular DNA receptor Z-DNA binding protein 1 (ZBP1). Activation of the mtDNA/ZBP1 pathway triggers the expression of pro-inflammatory markers in RPE cells. In addition, we show the enhanced release of extracellular vesicles (EVs) containing fragments of mtDNA derived from the apical site of RPE cells induces a pro-inflammatory phenotype of microglia via activation of ZBP1 signaling. Collectively, our report establishes oxidatively damaged mtDNA as an important signaling molecule with ZBP1 as its intracellular receptor in the development of an inflammatory response in the retina. We propose that this novel mtDNA-mediated autocrine and paracrine mechanism for triggering and maintaining inflammation in the retina may play an important role in ocular pathologies. Therefore, the molecular mechanisms identified in this report are potentially suitable therapeutic targets to ameliorate development of ocular pathologies.

Keywords: extracellular vesicles; microglia; mitochondrial DNA; oxidative stress; retinal pigment epithelial

DOI: https://doi.org/10.1016/j.jbc.2021.101523

Hum Mol Genet. 2021 Nov 23. pii: ddab341. [Epub ahead of print]

Genome-wide association study of mitochondrial copy number.

Manuel Gentiluomo, Matteo Giaccherini, Xīn Gào, Feng Guo, Hannah Stocker, Ben Schöttker, Hermann Brenner, Federico Canzian, Daniele Campa.

Mitochondrial DNA copy number (mtDNAcn) variation has been associated with increased risk of several human diseases in epidemiological studies. The quantification of mtDNAcn performed with real-time PCR is currently considered the de facto standard among several techniques. However, the heterogeneity of the laboratory methods (DNA extraction, storage, processing) used could give rise to results that are difficult to compare and reproduce across different studies. Several lines of evidence suggest that mtDNAcn is influenced by nuclear and mitochondrial genetic variability, however this relation is largely unexplored. The aim of this work was to elucidate the genetic basis of mtDNAcn variation. We performed a genome-wide association study (GWAS) of mtDNAcn in 6836 subjects from the ESTHER prospective cohort, and included, as replication set, the summary statistics of a GWAS that used 295 150 participants from the UK Biobank. We observed two novel associations with mtDNAcn variation on chromosome 19 (rs117176661), and 12 (rs7136238) that reached statistical significance at the genome-wide level. A polygenic score that we called mitoscore including all known single nucleotide polymorphisms explained 1.11% of the variation of mtDNAcn (p = 5.93 × 10-7). In conclusion, we performed a GWAS on mtDNAcn, adding to the evidence of the genetic background of this trait.

DOI: https://doi.org/10.1093/hmg/ddab341