bims-nenemi Biomed News
on Neuroinflammation, neurodegeneration and mitochondria
Issue of 2022–04–24
seven papers selected by
Marco Tigano, Thomas Jefferson University
  1. A tRNA processing enzyme is a key regulator of the mitochondrial unfolded protein response.
  2. Mitochondrial dynamics regulate genome stability via control of caspase-dependent DNA damage.
  3. Ceramide-induced integrated stress response overcomes Bcl-2 inhibitor resistance in acute myeloid leukemia.
  4. Organization and expression of the mammalian mitochondrial genome.
  5. mtDNA-STING Axis Mediates Microglial Polarization via IRF3/NF-κB Signaling After Ischemic Stroke.
  6. Structural basis of protein substrate processing by human mitochondrial high-temperature requirement A2 protease.
  7. Mitochondrial respiratory quiescence: A new model for examining the role of mitochondrial metabolism in development.
  1. Elife. 2022 Apr 22. pii: e71634. [Epub ahead of print]11
    A tRNA processing enzyme is a key regulator of the mitochondrial unfolded protein response.
    James P Held, Gaomin Feng, Benjamin R Saunders, Claudia V Pereria, Kristopher Burkewitz, Maulik R Patel.
      The mitochondrial unfolded protein response (UPRmt) has emerged as a predominant mechanism that preserves mitochondrial function. Consequently, multiple pathways likely exist to modulate UPRmt. We discovered that the tRNA processing enzyme, homolog of ELAC2 (HOE-1), is key to UPRmt regulation in Caenorhabditis elegans. We find that nuclear HOE-1 is necessary and sufficient to robustly activate UPRmt. We show that HOE-1 acts via transcription factors ATFS-1 and DVE-1 that are crucial for UPRmt. Mechanistically, we show that HOE-1 likely mediates its effects via tRNAs, as blocking tRNA export prevents HOE-1-induced UPRmt. Interestingly, we find that HOE-1 does not act via the integrated stress response, which can be activated by uncharged tRNAs, pointing towards its reliance on a new mechanism. Finally, we show that the subcellular localization of HOE-1 is responsive to mitochondrial stress and is subject to negative regulation via ATFS-1. Together, we have discovered a novel RNA-based cellular pathway that modulates UPRmt.
    Keywords:  C. elegans; cell biology
    DOI:  https://doi.org/10.7554/eLife.71634
  2. Dev Cell. 2022 Apr 14. pii: S1534-5807(22)00229-5. [Epub ahead of print]
    Mitochondrial dynamics regulate genome stability via control of caspase-dependent DNA damage.
    Kai Cao, Joel S Riley, Rosalie Heilig, Alfredo E Montes-Gómez, Esmee Vringer, Kevin Berthenet, Catherine Cloix, Yassmin Elmasry, David G Spiller, Gabriel Ichim, Kirsteen J Campbell, Andrew P Gilmore, Stephen W G Tait.
      Mitochondrial dysfunction is interconnected with cancer. Nevertheless, how defective mitochondria promote cancer is poorly understood. We find that mitochondrial dysfunction promotes DNA damage under conditions of increased apoptotic priming. Underlying this process, we reveal a key role for mitochondrial dynamics in the regulation of DNA damage and genome instability. The ability of mitochondrial dynamics to regulate oncogenic DNA damage centers upon the control of minority mitochondrial outer membrane permeabilization (MOMP), a process that enables non-lethal caspase activation leading to DNA damage. Mitochondrial fusion suppresses minority MOMP and its associated DNA damage by enabling homogeneous mitochondrial expression of anti-apoptotic BCL-2 proteins. Finally, we find that mitochondrial dysfunction inhibits pro-apoptotic BAX retrotranslocation, causing BAX mitochondrial localization and thereby promoting minority MOMP. Unexpectedly, these data reveal oncogenic effects of mitochondrial dysfunction that are mediated via mitochondrial dynamics and caspase-dependent DNA damage.
    Keywords:  DNA damage; MOMP; apoptosis; cancer; caspase; cell death; fission; fusion; mitochondrial dynamics
    DOI:  https://doi.org/10.1016/j.devcel.2022.03.019
  3. Blood. 2022 Apr 20. pii: blood.2021013277. [Epub ahead of print]
    Ceramide-induced integrated stress response overcomes Bcl-2 inhibitor resistance in acute myeloid leukemia.
    Alexander C Lewis, Victoria S Pope, Melinda N Tea, Manjun Li, Gus O Nwosu, Thao M Nguyen, Craig Thomas Wallington-Beddoe, Paul A Moretti, Dovile Anderson, Darren J Creek, Maurizio Costabile, Saira R Ali, Chloe Al Thompson-Peach, B Kate Dredge, Andrew G Bert, Gregory J Goodall, Paul G Ekert, Anna L Brown, Richard J D'Andrea, Nirmal Robinson, Melissa R Pitman, Daniel Thomas, David M Ross, Briony L Gliddon, Jason A Powell, Stuart M Pitson.
      Inducing cell death by the sphingolipid ceramide is a potential anti-cancer strategy, but the underlying mechanisms remain poorly defined. Here, we show that triggering accumulation of ceramide in acute myeloid leukaemia (AML) cells by inhibition of sphingosine kinase induces an apoptotic integrated stress response (ISR) through protein kinase R-mediated activation of the master transcription factor ATF4. This leads to transcription of the BH3-only protein, Noxa, and degradation of the pro-survival Mcl-1 protein on which AML cells are highly dependent on for survival. Targeting this novel ISR pathway in combination with the Bcl-2 inhibitor venetoclax synergistically killed primary AML blasts, including those with venetoclax-resistant mutations, as well as immunophenotypic leukemic stem cells, and reduced leukemic engraftment in patient-derived AML xenografts. Collectively, these findings provide mechanistic insight into the anti-cancer effects of ceramide and pre-clinical evidence for new approaches to augment Bcl-2 inhibition in the therapy of AML and other cancers with high Mcl-1 dependency.
    DOI:  https://doi.org/10.1182/blood.2021013277
  4. Nat Rev Genet. 2022 Apr 22.
    Organization and expression of the mammalian mitochondrial genome.
    Oliver Rackham, Aleksandra Filipovska.
      The mitochondrial genome encodes core subunits of the respiratory chain that drives oxidative phosphorylation and is, therefore, essential for energy conversion. Advances in high-throughput sequencing technologies and cryoelectron microscopy have shed light on the structure and organization of the mitochondrial genome and revealed unique mechanisms of mitochondrial gene regulation. New animal models of impaired mitochondrial protein synthesis have shown how the coordinated regulation of the cytoplasmic and mitochondrial translation machineries ensures the correct assembly of the respiratory chain complexes. These new technologies and disease models are providing a deeper understanding of mitochondrial genome organization and expression and of the diseases caused by impaired energy conversion, including mitochondrial, neurodegenerative, cardiovascular and metabolic diseases. They also provide avenues for the development of treatments for these conditions.
    DOI:  https://doi.org/10.1038/s41576-022-00480-x
  5. Front Immunol. 2022 ;13 860977
    mtDNA-STING Axis Mediates Microglial Polarization via IRF3/NF-κB Signaling After Ischemic Stroke.
    Lingqi Kong, Wenyu Li, E Chang, Wuxuan Wang, Nan Shen, Xiang Xu, Xinyue Wang, Yan Zhang, Wen Sun, Wei Hu, Pengfei Xu, Xinfeng Liu.
      Neuroinflammation is initiated in response to ischemic stroke, and is usually characterized by microglial activation and polarization. Stimulator of interferon genes (STING) has been shown to play a critical role in anti-tumor immunity and inflammatory diseases. Nevertheless, the effect and underlying mechanisms of STING on microglial polarization after ischemic stroke remain unclarified. In this study, acute ischemic stroke was simulated using a model of middle cerebral artery occlusion (MCAO) at adult male C57BL/6 mice in vivo and the BV2 microglia oxygen-glucose deprivation/reperfusion (OGD/R) model in vitro. The specific STING inhibitor C-176 was administered intraperitoneally at 30min after MCAO. We found that the expression of microglial STING was increased following MCAO and OGD/R. Pharmacologic inhibition of STING with C-176 reduced the ischemia/reperfusion (I/R)-induced brain infarction, edema and neuronal injury. Moreover, blockade of STING improved neurological performance and cognitive function and attenuated neuronal degeneration in the hippocampus after MCAO. Mechanistically, both in vivo and in vitro, we delineated that STING could promote the polarization of microglia towards the M1 phenotype and restrain M2 microglia polarization via downstream pathways, including interferon regulatory factor 3 (IRF3) and nuclear factor-κB (NF-κB). In addition, mitochondrial DNA (mtDNA), which is released to microglial cytoplasm induced by I/R injury, could facilitate microglia towards M1 modality through STING signaling pathway. Treatment with C-176 abolished the detrimental effects of mtDNA on stroke outcomes. Taken together, these findings suggest that STING, activated by mtDNA, could polarize microglia to the M1 phenotype following MCAO. Inhibition of STING may serve as a potential therapeutic strategy to mitigate neuroinflammation after ischemic stroke.
    Keywords:  STING; ischemia/reperfusion (I/R) injury; microglia; neuroinflammation; polarization
    DOI:  https://doi.org/10.3389/fimmu.2022.860977
  6. Proc Natl Acad Sci U S A. 2022 Apr 26. 119(17): e2203172119
    Structural basis of protein substrate processing by human mitochondrial high-temperature requirement A2 protease.
    Yuki Toyama, Robert W Harkness, Lewis E Kay.
      SignificanceProtein aggregates are often toxic, leading to impaired cellular activities and disease. The human HtrA2 trimeric enzyme cleaves such aggregates, and mutations in HtrA2 are causative for various neurodegenerative disorders, such as Parkinson's disease and essential tremor. The mechanism by which cleavage occurs has been studied using small peptides, but little information is available as to how HtrA2 protects cells from the pathologic effects of aggregation involving protein molecules that can form well-folded structures. Using solution NMR spectroscopy, we investigated the structural dynamics of the interaction between HtrA2 and a model protein substrate, demonstrating that HtrA2 preferentially binds to an unfolded substrate ensemble and providing insights into how HtrA2 function is regulated.
    Keywords:  conformational selection; ligand-binding thermodynamics; methyl transverse relaxation optimized NMR spectroscopy; mitochondrial proteostasis; protein–protein interaction
    DOI:  https://doi.org/10.1073/pnas.2203172119
  7. Semin Cell Dev Biol. 2022 Apr 18. pii: S1084-9521(22)00122-7. [Epub ahead of print]
    Mitochondrial respiratory quiescence: A new model for examining the role of mitochondrial metabolism in development.
    Helin Hocaoglu, Matthew Sieber.
      Mitochondria are vital organelles with a central role in all aspects of cellular metabolism. As a means to support the ever-changing demands of the cell, mitochondria produce energy, drive biosynthetic processes, maintain redox homeostasis, and function as a hub for cell signaling. While mitochondria have been widely studied for their role in disease and metabolic dysfunction, this organelle has a continually evolving role in the regulation of development, wound repair, and regeneration. Mitochondrial metabolism dynamically changes as tissues transition through distinct phases of development. These organelles support the energetic and biosynthetic demands of developing cells and function as key structures that coordinate the nutrient status of the organism with developmental progression. This review will examine the mechanisms that link mitochondria to developmental processes. We will also examine the process of mitochondrial respiratory quiescence (MRQ), a novel mechanism for regulating cellular metabolism through the biochemical and physiological remodeling of mitochondria. Lastly, we will examine MRQ as a system to discover the mechanisms that drive mitochondrial remodeling during development.
    Keywords:  Cancer; Drosophila; Metabolism; Mitochondria; Oocytes; Quiescence; Reprogramming; Stem cells
    DOI:  https://doi.org/10.1016/j.semcdb.2022.03.040
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