bims-minimp 2022-01-23 papers

on Mitochondria, innate immunity, proteostasis

Issue of 2022‒01‒23
eleven papers selected by
Hanna Salmonowicz
International Institute of Molecular Mechanisms and Machines of the Polish Academy of Sciences

Ageing exacerbates ribosome pausing to disrupt cotranslational proteostasis.
The cGAS-STING pathway drives type I IFN immunopathology in COVID-19.
Cellular senescence: all roads lead to mitochondria.
One-Carbon Metabolism: Pulling the Strings behind Aging and Neurodegeneration.
Brain-derived autophagosome profiling reveals the engulfment of nucleoid-enriched mitochondrial fragments by basal autophagy in neurons.
The Mysterious Multitude: Structural Perspective on the Accessory Subunits of Respiratory Complex I.
Selective localization of Mfn2 near PINK1 enables its preferential ubiquitination by Parkin on mitochondria.
Heat Shock Protein 90 as Therapeutic Target for CVDs and Heart Ageing.
Thioredoxin interacting protein, a key molecular switch between oxidative stress and sterile inflammation in cellular response.
Mitoribosomal small subunit maturation involves formation of initiation-like complexes.
Mitochondria-mediated oxidative stress during viral infection.

Nature. 2022 Jan 19.

Ageing exacerbates ribosome pausing to disrupt cotranslational proteostasis.

Kevin C Stein, Fabián Morales-Polanco, Joris van der Lienden, T Kelly Rainbolt, Judith Frydman.

Ageing is accompanied by a decline in cellular proteostasis, which underlies many age-related protein misfolding diseases1,2. Yet, how ageing impairs proteostasis remains unclear. As nascent polypeptides represent a substantial burden on the proteostasis network3, we hypothesized that altered translational efficiency during ageing could help to drive the collapse of proteostasis. Here we show that ageing alters the kinetics of translation elongation in both Caenorhabditis elegans and Saccharomyces cerevisiae. Ribosome pausing was exacerbated at specific positions in aged yeast and worms, including polybasic stretches, leading to increased ribosome collisions known to trigger ribosome-associated quality control (RQC)4-6. Notably, aged yeast cells exhibited impaired clearance and increased aggregation of RQC substrates, indicating that ageing overwhelms this pathway. Indeed, long-lived yeast mutants reduced age-dependent ribosome pausing, and extended lifespan correlated with greater flux through the RQC pathway. Further linking altered translation to proteostasis collapse, we found that nascent polypeptides exhibiting age-dependent ribosome pausing in C. elegans were strongly enriched among age-dependent protein aggregates. Notably, ageing increased the pausing and aggregation of many components of proteostasis, which could initiate a cycle of proteostasis collapse. We propose that increased ribosome pausing, leading to RQC overload and nascent polypeptide aggregation, critically contributes to proteostasis impairment and systemic decline during ageing.

DOI: https://doi.org/10.1038/s41586-021-04295-4
Nature. 2022 Jan 19.

The cGAS-STING pathway drives type I IFN immunopathology in COVID-19.

Jeremy Di Domizio, Muhammet F Gulen, Fanny Saidoune, Vivek V Thacker, Ahmad Yatim, Kunal Sharma, Théo Nass, Emmanuella Guenova, Martin Schaller, Curdin Conrad, Christine Goepfert, Laurence De Leval, Christophe von Garnier, Sabina Berezowska, Anaëlle Dubois, Michel Gilliet, Andrea Ablasser.

Coronavirus disease 2019 (COVID-19), caused by infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is characterized by significant lung pathology and extrapulmonary complications1,2. Type I interferons (IFNs) play an essential role in the pathogenesis of COVID-193-5. While rapid induction of type I IFNs limits virus propagation, sustained elevation of type I IFNs in the late phase of the infection is associated with aberrant inflammation and poor clinical outcome5-17. Here, we identify the cyclic GMP-AMP synthase (cGAS)-Stimulator of interferon genes (STING)-pathway, which controls immunity to cytosolic DNA, as a critical driver of aberrant type I IFN responses in COVID-1918. Profiling COVID-19 skin manifestations, we uncover a STING-dependent type I IFN signature primarily mediated by macrophages adjacent to areas of endothelial cell damage. Moreover, cGAS-STING activity was detected in lung samples of COVID-19 patients with prominent tissue destruction and associated with type I IFN responses. A lung-on-chip model revealed that, in addition to macrophages, SARS-CoV-2 infection activates cGAS-STING signalling in endothelial cells through mitochondrial DNA release, leading to cell death and type I IFN production. In mice, pharmacological inhibition of STING reduces severe lung inflammation induced by SARS-CoV-2 and improves disease outcome. Collectively, our study establishes a mechanistic basis of pathological type I IFN responses in COVID-19 and reveals a novel principle for the development of host-directed therapeutics.

DOI: https://doi.org/10.1038/s41586-022-04421-w
FEBS J. 2022 Jan 20.

Cellular senescence: all roads lead to mitochondria.

Hélène Martini, João F Passos.

  Senescence is a multi-functional cell fate, characterized by an irreversible cell-cycle arrest and a pro-inflammatory phenotype, commonly known as the Senescence-Associated secretory Phenotype (SASP). Emerging evidence indicates that accumulation of senescent cells in multiple tissues, drives tissue dysfunction and several age-related conditions. This has spurred the academic community and industry to identify new therapeutic interventions targeting this process. Mitochondrial dysfunction is an often-unappreciated hallmark of cellular senescence which plays important roles not only in the senescence growth arrest but also in the development of the SASP and resistance to cell-death. Here, we review the evidence that supports a role for mitochondria in the development of senescence and describe the underlying mechanisms. Finally, we propose that a detailed road map of mitochondrial biology in senescence will be crucial to guide the future development of senotherapies.

Keywords:  Mitochondria; SASP; aging; senescence

DOI:  https://doi.org/10.1111/febs.16361
Cells. 2022 Jan 09. pii: 214. [Epub ahead of print]11(2):

One-Carbon Metabolism: Pulling the Strings behind Aging and Neurodegeneration.

Eirini Lionaki, Christina Ploumi, Nektarios Tavernarakis.

  One-carbon metabolism (OCM) is a network of biochemical reactions delivering one-carbon units to various biosynthetic pathways. The folate cycle and methionine cycle are the two key modules of this network that regulate purine and thymidine synthesis, amino acid homeostasis, and epigenetic mechanisms. Intersection with the transsulfuration pathway supports glutathione production and regulation of the cellular redox state. Dietary intake of micronutrients, such as folates and amino acids, directly contributes to OCM, thereby adapting the cellular metabolic state to environmental inputs. The contribution of OCM to cellular proliferation during development and in adult proliferative tissues is well established. Nevertheless, accumulating evidence reveals the pivotal role of OCM in cellular homeostasis of non-proliferative tissues and in coordination of signaling cascades that regulate energy homeostasis and longevity. In this review, we summarize the current knowledge on OCM and related pathways and discuss how this metabolic network may impact longevity and neurodegeneration across species.

Keywords:  Alzheimer’s disease; Parkinson disease; aging; diet; folate; metabolism; methionine; mitochondria; neurodegeneration; one-carbon vitamins

DOI:  https://doi.org/10.3390/cells11020214
Neuron. 2022 Jan 13. pii: S0896-6273(21)01046-1. [Epub ahead of print]

Brain-derived autophagosome profiling reveals the engulfment of nucleoid-enriched mitochondrial fragments by basal autophagy in neurons.

Juliet Goldsmith, Alban Ordureau, J Wade Harper, Erika L F Holzbaur.

  Neurons depend on autophagy to maintain cellular homeostasis, and defects in autophagy are pathological hallmarks of neurodegenerative disease. To probe the role of basal autophagy in the maintenance of neuronal health, we isolated autophagic vesicles from mouse brain tissue and used proteomics to identify the major cargos engulfed within autophagosomes, validating our findings in rodent primary and human iPSC-derived neurons. Mitochondrial proteins were identified as a major cargo in the absence of mitophagy adaptors such as OPTN. We found that nucleoid-associated proteins are enriched compared with other mitochondrial components. In the axon, autophagic engulfment of nucleoid-enriched mitochondrial fragments requires the mitochondrial fission machinery Drp1. We proposed that localized Drp1-dependent fission of nucleoid-enriched fragments in proximity to the sites of autophagosome biogenesis enhances their capture. The resulting efficient autophagic turnover of nucleoids may prevent accumulation of mitochondrial DNA in the neuron, thus mitigating activation of proinflammatory pathways that contribute to neurodegeneration.

Keywords:  Drp1; TFAM; autophagy; mitochondria; mitochondrial division; mitochondrial nucleoids; mitophagy; neurodegeneration; neuronal homeostasis

DOI:  https://doi.org/10.1016/j.neuron.2021.12.029
Front Mol Biosci. 2021 ;8 798353

The Mysterious Multitude: Structural Perspective on the Accessory Subunits of Respiratory Complex I.

Abhilash Padavannil, Maria G Ayala-Hernandez, Eimy A Castellanos-Silva, James A Letts.

  Complex I (CI) is the largest protein complex in the mitochondrial oxidative phosphorylation electron transport chain of the inner mitochondrial membrane and plays a key role in the transport of electrons from reduced substrates to molecular oxygen. CI is composed of 14 core subunits that are conserved across species and an increasing number of accessory subunits from bacteria to mammals. The fact that adding accessory subunits incurs costs of protein production and import suggests that these subunits play important physiological roles. Accordingly, knockout studies have demonstrated that accessory subunits are essential for CI assembly and function. Furthermore, clinical studies have shown that amino acid substitutions in accessory subunits lead to several debilitating and fatal CI deficiencies. Nevertheless, the specific roles of CI's accessory subunits have remained mysterious. In this review, we explore the possible roles of each of mammalian CI's 31 accessory subunits by integrating recent high-resolution CI structures with knockout, assembly, and clinical studies. Thus, we develop a framework of experimentally testable hypotheses for the function of the accessory subunits. We believe that this framework will provide inroads towards the complete understanding of mitochondrial CI physiology and help to develop strategies for the treatment of CI deficiencies.

Keywords:  accessory subunits; electron transport chain; mitochondrial complex I; mitochondrial diseases; oxidative phosphorylation (OXPHOS)

DOI:  https://doi.org/10.3389/fmolb.2021.798353
Open Biol. 2022 Jan;12(1): 210255

Selective localization of Mfn2 near PINK1 enables its preferential ubiquitination by Parkin on mitochondria.

Marta Vranas, Yang Lu, Shafqat Rasool, Nathalie Croteau, Jonathan D Krett, Véronique Sauvé, Kalle Gehring, Edward A Fon, Thomas M Durcan, Jean-François Trempe.

  Mutations in Parkin and PINK1 cause early-onset familial Parkinson's disease. Parkin is a RING-In-Between-RING E3 ligase that transfers ubiquitin from an E2 enzyme to a substrate in two steps: (i) thioester intermediate formation on Parkin and (ii) acyl transfer to a substrate lysine. The process is triggered by PINK1, which phosphorylates ubiquitin on damaged mitochondria, which in turn recruits and activates Parkin. This leads to the ubiquitination of outer mitochondrial membrane proteins and clearance of the organelle. While the targets of Parkin on mitochondria are known, the factors determining substrate selectivity remain unclear. To investigate this, we examined how Parkin catalyses ubiquitin transfer to substrates. We found that His433 in the RING2 domain contributes to the catalysis of acyl transfer. In cells, the mutation of His433 impairs mitophagy. In vitro ubiquitination assays with isolated mitochondria show that Mfn2 is a kinetically preferred substrate. Using proximity-ligation assays, we show that Mfn2 specifically co-localizes with PINK1 and phospho-ubiquitin (pUb) in U2OS cells upon mitochondrial depolarization. We propose a model whereby ubiquitination of Mfn2 is efficient by virtue of its localization near PINK1, which leads to the recruitment and activation of Parkin via pUb at these sites.

Keywords:  Mfn2; PINK1; Parkin; mitochondria; ubiquitin

DOI:  https://doi.org/10.1098/rsob.210255
Int J Mol Sci. 2022 Jan 07. pii: 649. [Epub ahead of print]23(2):

Heat Shock Protein 90 as Therapeutic Target for CVDs and Heart Ageing.

Siarhei A Dabravolski, Vasily N Sukhorukov, Vladislav A Kalmykov, Nikolay A Orekhov, Andrey V Grechko, Alexander N Orekhov.

  Cardiovascular diseases (CVDs) are the leading cause of death globally, representing approximately 32% of all deaths worldwide. Molecular chaperones are involved in heart protection against stresses and age-mediated accumulation of toxic misfolded proteins by regulation of the protein synthesis/degradation balance and refolding of misfolded proteins, thus supporting the high metabolic demand of the heart cells. Heat shock protein 90 (HSP90) is one of the main cardioprotective chaperones, represented by cytosolic HSP90a and HSP90b, mitochondrial TRAP1 and ER-localised Grp94 isoforms. Currently, the main way to study the functional role of HSPs is the application of HSP inhibitors, which could have a different way of action. In this review, we discussed the recently investigated role of HSP90 proteins in cardioprotection, atherosclerosis, CVDs development and the involvements of HSP90 clients in the activation of different molecular pathways and signalling mechanisms, related to heart ageing.

Keywords:  ageing; atherosclerosis; cardiovascular diseases; chaperone; heat shock protein

DOI:  https://doi.org/10.3390/ijms23020649
World J Diabetes. 2021 Dec 15. 12(12): 1979-1999

Thioredoxin interacting protein, a key molecular switch between oxidative stress and sterile inflammation in cellular response.

Islam N Mohamed, Luling Li, Saifudeen Ismael, Tauheed Ishrat, Azza B El-Remessy.

  Tissue and systemic inflammation have been the main culprit behind the cellular response to multiple insults and maintaining homeostasis. Obesity is an independent disease state that has been reported as a common risk factor for multiple metabolic and microvascular diseases including nonalcoholic fatty liver disease (NAFLD), retinopathy, critical limb ischemia, and impaired angiogenesis. Sterile inflammation driven by high-fat diet, increased formation of reactive oxygen species, alteration of intracellular calcium level and associated release of inflammatory mediators, are the main common underlying forces in the pathophysiology of NAFLD, ischemic retinopathy, stroke, and aging brain. This work aims to examine the contribution of the pro-oxidative and pro-inflammatory thioredoxin interacting protein (TXNIP) to the expression and activation of NLRP3-inflammasome resulting in initiation or exacerbation of sterile inflammation in these disease states. Finally, the potential for TXNIP as a therapeutic target and whether TXNIP expression can be modulated using natural antioxidants or repurposing other drugs will be discussed.

Keywords:  High-fat diet; Inflammasome; Inflammation; Interleukin 1b; Ischemia; NOD-like receptor pyrin domain containing 3; Obesity; Oxidative stress; Reperfusion; Thioredoxin interacting protein

DOI:  https://doi.org/10.4239/wjd.v12.i12.1979
Proc Natl Acad Sci U S A. 2022 Jan 18. pii: e2114710118. [Epub ahead of print]119(3):

Mitoribosomal small subunit maturation involves formation of initiation-like complexes.

Tea Lenarčič, Moritz Niemann, David J F Ramrath, Salvatore Calderaro, Timo Flügel, Martin Saurer, Marc Leibundgut, Daniel Boehringer, Céline Prange, Elke K Horn, André Schneider, Nenad Ban.

  Mitochondrial ribosomes (mitoribosomes) play a central role in synthesizing mitochondrial inner membrane proteins responsible for oxidative phosphorylation. Although mitoribosomes from different organisms exhibit considerable structural variations, recent insights into mitoribosome assembly suggest that mitoribosome maturation follows common principles and involves a number of conserved assembly factors. To investigate the steps involved in the assembly of the mitoribosomal small subunit (mt-SSU) we determined the cryoelectron microscopy structures of middle and late assembly intermediates of the Trypanosoma brucei mitochondrial small subunit (mt-SSU) at 3.6- and 3.7-Å resolution, respectively. We identified five additional assembly factors that together with the mitochondrial initiation factor 2 (mt-IF-2) specifically interact with functionally important regions of the rRNA, including the decoding center, thereby preventing premature mRNA or large subunit binding. Structural comparison of assembly intermediates with mature mt-SSU combined with RNAi experiments suggests a noncanonical role of mt-IF-2 and a stepwise assembly process, where modular exchange of ribosomal proteins and assembly factors together with mt-IF-2 ensure proper 9S rRNA folding and protein maturation during the final steps of assembly.

Keywords:  mitochondria; ribosome assembly; structural biology; translation

DOI:  https://doi.org/10.1073/pnas.2114710118
Trends Microbiol. 2022 Jan 18. pii: S0966-842X(21)00318-8. [Epub ahead of print]

Mitochondria-mediated oxidative stress during viral infection.

Jonathan Foo, Gregory Bellot, Shazib Pervaiz, Sylvie Alonso.

  Through oxidative phosphorylation, mitochondria play a central role in energy production and are an important production source of reactive oxygen species (ROS). Not surprisingly, viruses have evolved to exploit this organelle in order to support their infection cycle. Beyond its role in the cellular antiviral response, induction of oxidative stress has emerged as a common strategy employed by many viruses to promote their replication. Here, we review the key molecular mechanisms employed by viruses to interact with mitochondria and induce oxidative stress. Furthermore, we discuss how viruses benefit from increased ROS levels, how they control ROS production to maintain a favorable redox environment, and how they cope with ROS-mediated cell death.

Keywords:  antioxidant therapy; electron transport chain (ETC); endoplasmic reticulum (ER) stress; intrinsic apoptosis; oxidative phosphorylation (OXPHOS); reactive oxygen species (ROS)

DOI:  https://doi.org/10.1016/j.tim.2021.12.011