bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2021‒05‒02
twelve papers selected by
Edmond Chan
Queen’s University, School of Medicine
  1. Cellular pyrimidine imbalance triggers mitochondrial DNA-dependent innate immunity.
  2. IFN-β rescues neurodegeneration by regulating mitochondrial fission via STAT5, PGAM5, and Drp1.
  3. Arginine and lysine methylation of MRPS23 promotes breast cancer metastasis through regulating OXPHOS.
  4. Inhibition of mitochondrial translation suppresses glioblastoma stem cell growth.
  5. PINK1-mediated mitophagy maintains pluripotency through optineurin.
  6. Mitochondrial Metabolism Regulation of T Cell-Mediated Immunity.
  7. Evolving concepts in NAD+ metabolism.
  8. Motor proteins at the mitochondria-cytoskeleton interface.
  9. Asparagine, a Key Metabolite in Cellular Response to Mitochondrial Dysfunction.
  10. Mitochondrial ATP-Dependent Proteases-Biological Function and Potential Anti-Cancer Targets.
  11. Succinate Anaplerosis Has an Onco-Driving Potential in Prostate Cancer Cells.
  12. Mitochondrial calcium at the synapse.
  1. Nat Metab. 2021 Apr 26.
    Cellular pyrimidine imbalance triggers mitochondrial DNA-dependent innate immunity.
    Hans-Georg Sprenger, Thomas MacVicar, Amir Bahat, Kai Uwe Fiedler, Steffen Hermans, Denise Ehrentraut, Katharina Ried, Dusanka Milenkovic, Nina Bonekamp, Nils-Göran Larsson, Hendrik Nolte, Patrick Giavalisco, Thomas Langer.
      Cytosolic mitochondrial DNA (mtDNA) elicits a type I interferon response, but signals triggering the release of mtDNA from mitochondria remain enigmatic. Here, we show that mtDNA-dependent immune signalling via the cyclic GMP-AMP synthase‒stimulator of interferon genes‒TANK-binding kinase 1 (cGAS-STING-TBK1) pathway is under metabolic control and is induced by cellular pyrimidine deficiency. The mitochondrial protease YME1L preserves pyrimidine pools by supporting de novo nucleotide synthesis and by proteolysis of the pyrimidine nucleotide carrier SLC25A33. Deficiency of YME1L causes inflammation in mouse retinas and in cultured cells. It drives the release of mtDNA and a cGAS-STING-TBK1-dependent inflammatory response, which requires SLC25A33 and is suppressed upon replenishment of cellular pyrimidine pools. Overexpression of SLC25A33 is sufficient to induce immune signalling by mtDNA. Similarly, depletion of cytosolic nucleotides upon inhibition of de novo pyrimidine synthesis triggers mtDNA-dependent immune responses in wild-type cells. Our results thus identify mtDNA release and innate immune signalling as a metabolic response to cellular pyrimidine deficiencies.
    DOI:  https://doi.org/10.1038/s42255-021-00385-9
  2. EMBO J. 2021 Apr 29. e106868
    IFN-β rescues neurodegeneration by regulating mitochondrial fission via STAT5, PGAM5, and Drp1.
    Emilie Tresse, Lluís Riera-Ponsati, Elham Jaberi, Wei Qi Guinevere Sew, Karsten Ruscher, Shohreh Issazadeh-Navikas.
      Mitochondrial homeostasis is essential for providing cellular energy, particularly in resource-demanding neurons, defects in which cause neurodegeneration, but the function of interferons (IFNs) in regulating neuronal mitochondrial homeostasis is unknown. We found that neuronal IFN-β is indispensable for mitochondrial homeostasis and metabolism, sustaining ATP levels and preventing excessive ROS by controlling mitochondrial fission. IFN-β induces events that are required for mitochondrial fission, phosphorylating STAT5 and upregulating PGAM5, which phosphorylates serine 622 of Drp1. IFN-β signaling then recruits Drp1 to mitochondria, oligomerizes it, and engages INF2 to stabilize mitochondria-endoplasmic reticulum (ER) platforms. This process tethers damaged mitochondria to the ER to separate them via fission. Lack of neuronal IFN-β in the Ifnb-/- model of Parkinson disease (PD) disrupts STAT5-PGAM5-Drp1 signaling, impairing fission and causing large multibranched, damaged mitochondria with insufficient ATP production and excessive oxidative stress to accumulate. In other PD models, IFN-β rescues dopaminergic neuronal cell death and pathology, associated with preserved mitochondrial homeostasis. Thus, IFN-β activates mitochondrial fission in neurons through the pSTAT5/PGAM5/S622 Drp1 pathway to stabilize mitochondria/ER platforms, constituting an essential neuroprotective mechanism.
    Keywords:  ATP; Parkinson disease; ROS; hydroxydopamine; mitochondrial metabolism
    DOI:  https://doi.org/10.15252/embj.2020106868
  3. Oncogene. 2021 Apr 29.
    Arginine and lysine methylation of MRPS23 promotes breast cancer metastasis through regulating OXPHOS.
    Lingxia Liu, Xiliu Zhang, Huayi Ding, Xin Liu, Donghui Cao, Yingqi Liu, Jiwei Liu, Cong Lin, Na Zhang, Guannan Wang, Jingyao Hou, Baiqu Huang, Yu Zhang, Jun Lu.
      Mitochondrial oxidative phosphorylation (OXPHOS) is a vital regulator of tumor metastasis. However, the mechanisms governing OXPHOS to facilitate tumor metastasis remain unclear. In this study, we discovered that arginine 21(R21) and lysine 108 (K108) of mitochondrial ribosomal protein S23 (MRPS23) was methylated by the protein arginine methyltransferase 7 (PRMT7) and SET-domain-containing protein 6 (SETD6), respectively. R21 methylation accelerated the poly-ubiquitin-dependent degradation of MRPS23 to a low level. The MRPS23 degradation inhibited OXPHOS with elevated mtROS level, which consequently increased breast cancer cell invasion and metastasis. In contrast, K108 methylation increased MRPS23 stability, and K108 methylation coordinated with R21 methylation to maintain a low level of MRPS23, which was in favor of supporting breast cancer cell survival through regulating OXPHOS. Consistently, R21 and K108 methylation was correlated with malignant breast carcinoma. Significantly, our findings unveil a unique mechanism of controlling OXPHOS by arginine and lysine methylation and point to the impact of the PRMT7-SETD6-MRPS23 axis during breast cancer metastasis.
    DOI:  https://doi.org/10.1038/s41388-021-01785-7
  4. Cell Rep. 2021 Apr 27. pii: S2211-1247(21)00338-7. [Epub ahead of print]35(4): 109024
    Inhibition of mitochondrial translation suppresses glioblastoma stem cell growth.
    Denise Sighel, Michela Notarangelo, Shintaro Aibara, Angela Re, Gianluca Ricci, Marianna Guida, Alessia Soldano, Valentina Adami, Chiara Ambrosini, Francesca Broso, Emanuele Filiberto Rosatti, Sara Longhi, Mariachiara Buccarelli, Quintino G D'Alessandris, Stefano Giannetti, Simone Pacioni, Lucia Ricci-Vitiani, Joanna Rorbach, Roberto Pallini, Sandrine Roulland, Alexey Amunts, Ines Mancini, Angelika Modelska, Alessandro Quattrone.
      Glioblastoma stem cells (GSCs) resist current glioblastoma (GBM) therapies. GSCs rely highly on oxidative phosphorylation (OXPHOS), whose function requires mitochondrial translation. Here we explore the therapeutic potential of targeting mitochondrial translation and report the results of high-content screening with putative blockers of mitochondrial ribosomes. We identify the bacterial antibiotic quinupristin/dalfopristin (Q/D) as an effective suppressor of GSC growth. Q/D also decreases the clonogenicity of GSCs in vitro, consequently dysregulating the cell cycle and inducing apoptosis. Cryoelectron microscopy (cryo-EM) reveals that Q/D binds to the large mitoribosomal subunit, inhibiting mitochondrial protein synthesis and functionally dysregulating OXPHOS complexes. These data suggest that targeting mitochondrial translation could be explored to therapeutically suppress GSC growth in GBM and that Q/D could potentially be repurposed for cancer treatment.
    Keywords:  OXPHOS; cryo-EM; dalfopristin; drug repurposing; glioblastoma; glioblastoma stem cells; high-content screening; mitochondrial translation; mitoribosome; quinupristin
    DOI:  https://doi.org/10.1016/j.celrep.2021.109024
  5. Cell Prolif. 2021 May 01. e13034
    PINK1-mediated mitophagy maintains pluripotency through optineurin.
    Chaoqun Wang, Kun Liu, Jiani Cao, Liang Wang, Qian Zhao, Zheng Li, Honghai Zhang, Quan Chen, Tongbiao Zhao.
      OBJECTIVES: Dysfunction of autophagy results in accumulation of depolarized mitochondria and breakdown of self-renewal and pluripotency in ESCs. However, the regulators that control how mitochondria are degraded by autophagy for pluripotency regulation remains largely unknown. This study aims to dissect the molecular mechanisms that regulate mitochondrial homeostasis for pluripotency regulation in mouse ESCs.MATERIALS AND METHODS: Parkin+/+ and parkin-/- ESCs were established from E3.5 blastocysts of parkin+/- x parkin+/- mating mice. The pink1-/- , optn-/- and ndp52-/- ESCs were generated by CRISPR-Cas9. shRNAs were used for function loss assay of target genes. Mito-Keima, ROS and ATP detection were used to investigate the mitophagy and mitochondrial function. Western blot, Q-PCR, AP staining and teratoma formation assay were performed to evaluate the PSC stemness.
    RESULTS: PINK1 or OPTN depletion impairs the degradation of dysfunctional mitochondria during reprogramming, and reduces the reprogramming efficiency and quality. In ESCs, PINK1 or OPTN deficiency leads to accumulation of dysfunctional mitochondria and compromised pluripotency. The defective mitochondrial homeostasis and pluripotency in pink1-/- ESCs can be compensated by gain expression of phosphomimetic Ubiquitin (Ub-S65D) together with WT or a constitutively active phosphomimetic OPTN mutant (S187D, S476D, S517D), rather than constitutively inactive OPTN (S187A, S476A, S517A) or a Ub-binding dead OPTN mutant (D477N).
    CONCLUSIONS: The mitophagy receptor OPTN guards ESC mitochondrial homeostasis and pluripotency by scavenging damaged mitochondria through TBK1-activated OPTN binding of PINK1-phosphorylated Ubiquitin.
    Keywords:  OPTN; PINK1; embryonic stem cells; mitochondria; mitophagy; reprogramming
    DOI:  https://doi.org/10.1111/cpr.13034
  6. Annu Rev Immunol. 2021 Apr 26. 39 395-416
    Mitochondrial Metabolism Regulation of T Cell-Mediated Immunity.
    Elizabeth M Steinert, Karthik Vasan, Navdeep S Chandel.
      Recent evidence supports the notion that mitochondrial metabolism is necessary for T cell activation, proliferation, and function. Mitochondrial metabolism supports T cell anabolism by providing key metabolites for macromolecule synthesis and generating metabolites for T cell function. In this review, we focus on how mitochondrial metabolism controls conventional and regulatory T cell fates and function.
    Keywords:  ROS; TCA cycle; acetyl-CoA; epigenetics; inflammation; l-2-hydroxyglutarate; l-2HG
    DOI:  https://doi.org/10.1146/annurev-immunol-101819-082015
  7. Cell Metab. 2021 Apr 22. pii: S1550-4131(21)00169-8. [Epub ahead of print]
    Evolving concepts in NAD+ metabolism.
    Claudia C S Chini, Julianna D Zeidler, Sonu Kashyap, Gina Warner, Eduardo Nunes Chini.
      NAD(H) and NADP(H) have traditionally been viewed as co-factors (or co-enzymes) involved in a myriad of oxidation-reduction reactions including the electron transport in the mitochondria. However, NAD pathway metabolites have many other important functions, including roles in signaling pathways, post-translational modifications, epigenetic changes, and regulation of RNA stability and function via NAD-capping of RNA. Non-oxidative reactions ultimately lead to the net catabolism of these nucleotides, indicating that NAD metabolism is an extremely dynamic process. In fact, recent studies have clearly demonstrated that NAD has a half-life in the order of minutes in some tissues. Several evolving concepts on the metabolism, transport, and roles of these NAD pathway metabolites in disease states such as cancer, neurodegeneration, and aging have emerged in just the last few years. In this perspective, we discuss key recent discoveries and changing concepts in NAD metabolism and biology that are reshaping the field. In addition, we will pose some open questions in NAD biology, including why NAD metabolism is so fast and dynamic in some tissues, how NAD and its precursors are transported to cells and organelles, and how NAD metabolism is integrated with inflammation and senescence. Resolving these questions will lead to significant advancements in the field.
    Keywords:  NAD pathway metabolites; NAD(+); aging; disease; humans; mitochondria; transport; vitamin B3
    DOI:  https://doi.org/10.1016/j.cmet.2021.04.003
  8. J Cell Sci. 2021 Apr 01. pii: jcs226084. [Epub ahead of print]134(7):
    Motor proteins at the mitochondria-cytoskeleton interface.
    Antonina J Kruppa, Folma Buss.
      Mitochondria are multifunctional organelles that not only produce energy for the cell, but are also important for cell signalling, apoptosis and many biosynthetic pathways. In most cell types, they form highly dynamic networks that are constantly remodelled through fission and fusion events, repositioned by motor-dependent transport and degraded when they become dysfunctional. Motor proteins and their tracks are key regulators of mitochondrial homeostasis, and in this Review, we discuss the diverse functions of the three classes of motor proteins associated with mitochondria - the actin-based myosins, as well as the microtubule-based kinesins and dynein. In addition, Miro and TRAK proteins act as adaptors that link kinesin-1 and dynein, as well as myosin of class XIX (MYO19), to mitochondria and coordinate microtubule- and actin-based motor activities. Here, we highlight the roles of motor proteins and motor-linked track dynamics in the transporting and docking of mitochondria, and emphasize their adaptations in specialized cells. Finally, we discuss how motor-cargo complexes mediate changes in mitochondrial morphology through fission and fusion, and how they modulate the turnover of damaged organelles via quality control pathways, such as mitophagy. Understanding the importance of motor proteins for mitochondrial homeostasis will help to elucidate the molecular basis of a number of human diseases.
    Keywords:  Actin; Dynein; Kinesin; Microtubules; Mitochondria; Myosin
    DOI:  https://doi.org/10.1242/jcs.226084
  9. Trends Cancer. 2021 Apr 22. pii: S2405-8033(21)00081-9. [Epub ahead of print]
    Asparagine, a Key Metabolite in Cellular Response to Mitochondrial Dysfunction.
    Yuyang Liu, Kıvanç Birsoy.
      The mitochondrial electron transport chain (ETC) has been an attractive target for cancer therapy due to its essentiality for tumor growth. Krall et al. found that under ETC dysfunction, a decrease in asparagine limits cancer cell proliferation and activates the integrated stress response, creating a therapeutically exploitable metabolic vulnerability.
    DOI:  https://doi.org/10.1016/j.trecan.2021.04.001
  10. Cancers (Basel). 2021 Apr 22. pii: 2020. [Epub ahead of print]13(9):
    Mitochondrial ATP-Dependent Proteases-Biological Function and Potential Anti-Cancer Targets.
    Yue Feng, Kazem Nouri, Aaron D Schimmer.
      Cells must eliminate excess or damaged proteins to maintain protein homeostasis. To ensure protein homeostasis in the cytoplasm, cells rely on the ubiquitin-proteasome system and autophagy. In the mitochondria, protein homeostasis is regulated by mitochondria proteases, including four core ATP-dependent proteases, m-AAA, i-AAA, LonP, and ClpXP, located in the mitochondrial membrane and matrix. This review will discuss the function of mitochondrial proteases, with a focus on ClpXP as a novel therapeutic target for the treatment of malignancy. ClpXP maintains the integrity of the mitochondrial respiratory chain and regulates metabolism by degrading damaged and misfolded mitochondrial proteins. Inhibiting ClpXP genetically or chemically impairs oxidative phosphorylation and is toxic to malignant cells with high ClpXP expression. Likewise, hyperactivating the protease leads to increased degradation of ClpXP substrates and kills cancer cells. Thus, targeting ClpXP through inhibition or hyperactivation may be novel approaches for patients with malignancy.
    Keywords:  AML; ClpXP; cancer; mitochondria; protease
    DOI:  https://doi.org/10.3390/cancers13092020
  11. Cancers (Basel). 2021 Apr 06. pii: 1727. [Epub ahead of print]13(7):
    Succinate Anaplerosis Has an Onco-Driving Potential in Prostate Cancer Cells.
    Ana Carolina B Sant'Anna-Silva, Juan A Perez-Valencia, Marco Sciacovelli, Claude Lalou, Saharnaz Sarlak, Laura Tronci, Efterpi Nikitopoulou, Andras T Meszaros, Christian Frezza, Rodrigue Rossignol, Erich Gnaiger, Helmut Klocker.
      Tumor cells display metabolic alterations when compared to non-transformed cells. These characteristics are crucial for tumor development, maintenance and survival providing energy supplies and molecular precursors. Anaplerosis is the property of replenishing the TCA cycle, the hub of carbon metabolism, participating in the biosynthesis of precursors for building blocks or signaling molecules. In advanced prostate cancer, an upshift of succinate-driven oxidative phosphorylation via mitochondrial Complex II was reported. Here, using untargeted metabolomics, we found succinate accumulation mainly in malignant cells and an anaplerotic effect contributing to biosynthesis, amino acid, and carbon metabolism. Succinate also stimulated oxygen consumption. Malignant prostate cells displayed higher mitochondrial affinity for succinate when compared to non-malignant prostate cells and the succinate-driven accumulation of metabolites induced expression of mitochondrial complex subunits and their activities. Moreover, extracellular succinate stimulated migration, invasion, and colony formation. Several enzymes linked to accumulated metabolites in the malignant cells were found upregulated in tumor tissue datasets, particularly NME1 and SHMT2 mRNA expression. High expression of the two genes was associated with shorter disease-free survival in prostate cancer cohorts. Moreover, in-vitro expression of both genes was enhanced in prostate cancer cells upon succinate stimulation. In conclusion, the data indicate that uptake of succinate from the tumor environment has an anaplerotic effect that enhances the malignant potential of prostate cancer cells.
    Keywords:  anaplerosis; cancer metabolism; mitochondria; prostate cancer; succinate
    DOI:  https://doi.org/10.3390/cancers13071727
  12. Mitochondrion. 2021 Apr 22. pii: S1567-7249(21)00052-0. [Epub ahead of print]
    Mitochondrial calcium at the synapse.
    Sayantan Datta, Manish Jaiswal.
      Mitochondria are dynamic organelles, which serve various purposes, including but not limited to the production of ATP and various metabolites, buffering ions, acting as a signaling hub, etc. In recent years, mitochondria are being seen as the central regulators of cellular growth, development, and death. Since neurons are highly specialized cells with a heavy metabolic demand, it is not surprising that neurons are one of the most mitochondria-rich cells in an animal. At synapses, mitochondrial function and dynamics is tightly regulated by synaptic calcium. Calcium influx during synaptic activity causes increased mitochondrial calcium influx leading to an increased ATP production as well as buffering of synaptic calcium. While increased ATP production is required during synaptic transmission, calcium buffering by mitochondria is crucial to prevent faulty neurotransmission and excitotoxicity. Interestingly, mitochondrial calcium also regulates the mobility of mitochondria within synapses causing mitochondria to halt at the synapse during synaptic transmission. In this review, we summarize the various roles of mitochondrial calcium at the synapse.
    Keywords:  LETM1; MCU; Mitochondrial Calcium Efflux; Mitochondrial Calcium Influx; NCLX; Synaptic Calcium; VDAC
    DOI:  https://doi.org/10.1016/j.mito.2021.04.006
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