bims-minimp 2021-12-19 papers

on Mitochondria, innate immunity, proteostasis

Issue of 2021–12–19
nine papers selected by
Hanna Salmonowicz, International Institute of Molecular Mechanisms and Machines of the Polish Academy of Sciences

Cristae junction as a fundamental switchboard for mitochondrial ion signaling and bioenergetics.
Cytoplasmic innate immune sensing by the caspase-4 non-canonical inflammasome promotes cellular senescence.
TRAP1 inhibits MIC60 ubiquitination to mitigate the injury of cardiomyocytes and protect mitochondria in extracellular acidosis.
New Insights Into the Role of Mitochondria Quality Control in Ischemic Heart Disease.
Identification of uncharacterized proteins potentially localized to mitochondria (UPMs) in S. cerevisiae using a fluorescent protein unstable in the cytoplasm.
An alternatively spliced STING isoform localizes in the cytoplasmic membrane and directly senses extracellular cGAMP.
Lack of transcriptional coordination between mitochondrial and nuclear oxidative phosphorylation genes in the presence of two divergent mitochondrial genomes.
Why do cells need oxygen? Insights from mitochondrial composition and function.
The evolution of innate immune receptors: investigating the diversity, distribution, and phylogeny of immune recognition across eukaryotes.

Cell Calcium. 2021 Dec 10. pii: S0143-4160(21)00171-8. [Epub ahead of print]101 102517

Cristae junction as a fundamental switchboard for mitochondrial ion signaling and bioenergetics.

Benjamin Gottschalk, Corina T Madreiter-Sokolowski, Wolfgang F Graier.

OPA1 and MICU1 are both involved in the regulation of mitochondrial Ca2+ uptake and the stabilization of the cristae junction, which separates the inner mitochondrial membrane into the interboundary membrane and the cristae membrane. In this mini-review, we focus on the synergetic control of OPA1 and MICU1 on the cristae junction that serves as a fundamental regulator of multiple mitochondrial functions. In particular, we point to the critical role of an adaptive cristae junction permeability in mitochondrial Ca2+ signaling, spatial H+ gradients and mitochondrial membrane potential, metabolic activity, and apoptosis. These characteristics bear on a distinct localization of the oxidative phosphorylation machinery, the FoF1-ATPase, and mitochondrial Ca2+uniporter (MCU) within sections of the inner mitochondrial membrane isolated by the cristae junction and regulated by proteins like OPA1 and MICU1. We specifically focus on the impact of MICU1-regulated cristae junction on the activity and distribution of MCU within the complex ultrastructure of mitochondria.

DOI: https://doi.org/10.1016/j.ceca.2021.102517
Cell Death Differ. 2021 Dec 16.

Cytoplasmic innate immune sensing by the caspase-4 non-canonical inflammasome promotes cellular senescence.

Irene Fernández-Duran, Andrea Quintanilla, Núria Tarrats, Jodie Birch, Priya Hari, Fraser R Millar, Anthony B Lagnado, Vanessa Smer-Barreto, Morwenna Muir, Valerie G Brunton, João F Passos, Juan Carlos Acosta.

Cytoplasmic recognition of microbial lipopolysaccharides (LPS) in human cells is elicited by the caspase-4 and caspase-5 noncanonical inflammasomes, which induce a form of inflammatory cell death termed pyroptosis. Here we show that LPS-mediated activation of caspase-4 also induces a stress response promoting cellular senescence, which is dependent on the caspase-4 substrate gasdermin-D and the tumor suppressor p53. Furthermore, we found that the caspase-4 noncanonical inflammasome is induced and assembled in response to oncogenic RAS signaling during oncogene-induced senescence (OIS). Moreover, targeting caspase-4 expression in OIS showed its critical role in the senescence-associated secretory phenotype and the cell cycle arrest induced in cellular senescence. Finally, we observed that caspase-4 induction occurs in vivo in mouse models of tumor suppression and ageing. Altogether, we are showing that cellular senescence is induced by cytoplasmic LPS recognition by the noncanonical inflammasome and that this pathway is conserved in the cellular response to oncogenic stress.

DOI: https://doi.org/10.1038/s41418-021-00917-6
Cell Death Discov. 2021 Dec 14. 7(1): 389

TRAP1 inhibits MIC60 ubiquitination to mitigate the injury of cardiomyocytes and protect mitochondria in extracellular acidosis.

Lingxiao Zhang, Ning Su, Yuanyuan Luo, Siyin Chen, Tongfeng Zhao.

Extracellular acidosis-induced mitochondrial damage of cardiomyocytes leads to cardiac dysfunction, but no detailed mechanism or efficient therapeutic target has been reported. Here we found that the protein levels of MIC60 were decreased in H9C2 cells and heart tissues in extracellular acidosis, which caused mitochondrial damage and cardiac dysfunction. Overexpression of MIC60 maintains H9C2 cells viability, increases ATP production and mitochondrial membrane potential, mitigates the disruptions of mitochondrial structure and cardiac injury. Mechanistically, extracellular acidosis excessively promoted MIC60 ubiquitin-dependent degradation. TRAP1 mitigated acidosis-induced mitochondrial impairments and cardiac injury by directly interacting with MIC60 to decrease its ubiquitin-dependent degradation in extracellular acidosis.

DOI: https://doi.org/10.1038/s41420-021-00786-5
Front Cardiovasc Med. 2021 ;8 774619

New Insights Into the Role of Mitochondria Quality Control in Ischemic Heart Disease.

Yanguo Xin, Xiaodong Zhang, Jingye Li, Hui Gao, Jiayu Li, Junli Li, Wenyu Hu, Hongwei Li.

  IHD is a significant cause of mortality and morbidity worldwide. In the acute phase, it's demonstrated as myocardial infarction and ischemia-reperfusion injury, while in the chronic stage, the ischemic heart is mainly characterised by adverse myocardial remodelling. Although interventions such as thrombolysis and percutaneous coronary intervention could reduce the death risk of these patients, the underlying cellular and molecular mechanisms need more exploration. Mitochondria are crucial to maintain the physiological function of the heart. During IHD, mitochondrial dysfunction results in the pathogenesis of ischemic heart disease. Ischemia drives mitochondrial damage not only due to energy deprivation, but also to other aspects such as mitochondrial dynamics, mitochondria-related inflammation, etc. Given the critical roles of mitochondrial quality control in the pathological process of ischemic heart disease, in this review, we will summarise the efforts in targeting mitochondria (such as mitophagy, mtROS, and mitochondria-related inflammation) on IHD. In addition, we will briefly revisit the emerging therapeutic targets in this field.

Keywords:  inflammation; metabolism; mitochondria; myocardial infarction; remodelling

DOI:  https://doi.org/10.3389/fcvm.2021.774619
Yeast. 2021 Dec 15.

Identification of uncharacterized proteins potentially localized to mitochondria (UPMs) in S. cerevisiae using a fluorescent protein unstable in the cytoplasm.

Satoshi Horiuchi, Shotaro Namba, Nozomu Saeki, Ayano Satoh, Hisao Moriya.

  Eukaryotic cells are composed of organelles, and each organelle contains proteins that play a role in its function. Therefore, the localization of a protein, especially to organelles, is a clue to infer the function of that protein. In this study, we attempted to identify novel mitochondrially localized proteins in the budding yeast S. cerevisiae using a fluorescent protein (GFPdeg) that is rapidly degraded in the cytoplasm. Of the budding yeast proteins predicted to localize to mitochondria by the prediction tool Deeploc-1.0, those with known mitochondrial localization or functional relevance were eliminated, and 95 proteins of unknown function were selected as candidates for analysis. By forced expression of GFPdeg fusion proteins with these proteins and observation of their localization, we identified 35 uncharacterized proteins potentially localized to mitochondria (UPMs). Most of these had no N-terminal mitochondrial localization signal and were evolutionarily young "emerging genes" that exist only in S. cerevisiae. Some of these genes were found to be upregulated during the post-diauxic shift phase when mitochondria are being developed, suggesting that they are actually involved in some mitochondrial function.

Keywords:  S. cerevisiae; emerging ORFs; mitochondria

DOI:  https://doi.org/10.1002/yea.3685
J Clin Invest. 2021 Dec 14. pii: e144339. [Epub ahead of print]

An alternatively spliced STING isoform localizes in the cytoplasmic membrane and directly senses extracellular cGAMP.

Xiaobo Li, Yuanyuan Zhu, Xiao Zhang, Xiang An, Mingjiao Weng, Jiaqi Shi, Song Wang, Caiqi Liu, Shengnan Luo, Tongsen Zheng.

  It has been revealed that 2'3'-cyclic-GMP-AMP (cGAMP), a second messenger that activates the antiviral stimulator of interferon genes (STING), elicits an antitumoral immune response. Since cGAMP cannot cross the cell membrane, it is not clear how intracellular STING has been activated by extracellular cGAMP until SLC19A1 was identiﬁed as an importer to transport extracellular cGAMP into cytosol. However, SLC19A1 deficient cells also sense extracellular cGAMP, suggesting the presence of mechanisms other than the facilitating transporters for STING sensing extracellular cGAMP. Here, we identified an alternatively spliced STING isoform (plasmatic membrane STING, pmSTING) that localized in the plasma membrane with its C-terminus outside the cell, due to lack of one transmembrane domain in its N-terminus compared to canonical STING, by using immunoprecipitation, immunofluorescence and flow cytometry. Further studies showed that extracellular cGAMP not only promoted the dimerization of pmSTING and interaction of pmSTING with Tank-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3), but also enhanced the phosphorylation of TBK1 and IRF3 and production of interferon in pmSTING transfected cells. Additionally, we also identified similar pmSTING isoforms in other animal species including human. This study suggests a conserved role for pmSTING in sensing extracellular cGAMP and provides insight into cGAMP's role as an immunotransmitter.

Keywords:  Cancer immunotherapy; Cellular immune response; Immunology; Innate immunity; Oncology

DOI:  https://doi.org/10.1172/JCI144339
Zool Res. 2022 Jan 18. pii: 2095-8137(2022)01-0111-18. [Epub ahead of print]43(1): 111-128

Lack of transcriptional coordination between mitochondrial and nuclear oxidative phosphorylation genes in the presence of two divergent mitochondrial genomes.

Ran Xu, Mariangela Iannello, Justin C Havird, Liliana Milani, Fabrizio Ghiselli.

  In most eukaryotes, oxidative phosphorylation (OXPHOS) is the main energy production process and it involves both mitochondrial and nuclear genomes. The close interaction between the two genomes is critical for the coordinated function of the OXPHOS process. Some bivalves show doubly uniparental inheritance (DUI) of mitochondria, where two highly divergent mitochondrial genomes, one inherited through eggs (F-type) and the other through sperm (M-type), coexist in the same individual. However, it remains a puzzle how nuclear OXPHOS genes coordinate with two divergent mitochondrial genomes in DUI species. In this study, we compared transcription, polymorphism, and synonymous codon usage in the mitochondrial and nuclear OXPHOS genes of the DUI species Ruditapes philippinarum using sex- and tissue-specific transcriptomes. Mitochondrial and nuclear OXPHOS genes showed different transcription profiles. Strong co-transcription signal was observed within mitochondrial (separate for F- and M-type) and within nuclear OXPHOS genes but the signal was weak or absent between mitochondrial and nuclear OXPHOS genes, suggesting that the coordination between mitochondrial and nuclear OXPHOS subunits is not achieved transcriptionally. McDonald-Kreitman and frequency-spectrum based tests indicated that M-type OXPHOS genes deviated significantly from neutrality, and that F-type and M-type OXPHOS genes undergo different selection patterns. Codon usage analysis revealed that mutation bias and translational selection were the major factors affecting the codon usage bias in different OXPHOS genes, nevertheless, translational selection in mitochondrial OXPHOS genes appears to be less efficient than nuclear OXPHOS genes. Therefore, we speculate that the coordination between OXPHOS genes may involve post-transcriptional/translational regulation.

Keywords:  Co-transcription; Codon usage bias; Doubly uniparental inheritance; Oxidative phosphorylation; Polymorphism; Translational selection

DOI:  https://doi.org/10.24272/j.issn.2095-8137.2021.348
Cell Biol Int. 2021 Dec 17.

Why do cells need oxygen? Insights from mitochondrial composition and function.

Kelath Murali Manoj, Daniel Andrew Gideon, Laurent Jaeken.

  Mitochondrial membrane-embedded redox proteins are classically perceived as deterministic 'electron transport chain' (ETC) arrays cum proton pumps; and oxygen is seen as an 'immobile terminal electron acceptor'. This is untenable because: (1) there are little free protons to be pumped out of the matrix; (2) proton pumping would be highly endergonic; (3) ETC-chemiosmosis-rotary ATP synthesis proposal is 'irreducibly complex'/'non-evolvable' and does not fit with mitochondrial architecture or structural/distribution data of the concerned proteins/components; (4) a plethora of experimental observations do not conform to the postulates/requisites; e.g. there is little evidence for viable proton-pumps/pH-gradient in mitochondria, trans-membrane potential (TMP) is non-fluctuating/non-trappable, oxygen is seen to give copious 'diffusible reactive (oxygen) species' (DRS/DROS) in milieu, etc. Quite contrarily, the newly proposed murburn model's tenets agree with known principles of energetics/kinetics, and build on established structural data and reported observations. In this purview, oxygen is needed to make DRS, the principal component of mitochondrial function. Complex V and porins respectively serve as proton-inlet and turgor-based water-exodus portals, thereby achieving organellar homeostasis. Complexes I to IV possess ADP-binding sites and their redox-centres react/interact with O2 /DRS. At/around these complexes, DRS cross-react or activate/oxidize ADP/Pi via fast thermogenic one-electron reaction(s), condensing to form two-electron stabilized products (H2 O2 /H2 O/ATP). The varied architecture and distribution of components in mitochondria validate DRS as the- (i) the coupling agent of oxidative reactions and phosphorylations, and (ii) the primary reason for manifestation of TMP in steady-state. Explorations along the new precepts stand to provide greater insights on mitochondrial function and pathophysiology. This article is protected by copyright. All rights reserved.

Keywords:  energetics; homeostasis; mitochondrial physiology; murburn concept; thermogenesis

DOI:  https://doi.org/10.1002/cbin.11746
Immunogenetics. 2021 Dec 15.

The evolution of innate immune receptors: investigating the diversity, distribution, and phylogeny of immune recognition across eukaryotes.

Katherine M Buckley, Jeffrey A Yoder.

DOI: https://doi.org/10.1007/s00251-021-01243-4