bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2023–09–17
nine papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. Molecular pathway of mitochondrial preprotein import through the TOM-TIM23 supercomplex.
  2. The heat shock protein Hsp27 controls mitochondrial function by modulating ceramide generation.
  3. A STAT3 protein complex required for mitochondrial mRNA stability and cancer.
  4. Mitochondrial GTP metabolism controls reproductive aging in C. elegans.
  5. Mitochondria Derived Vesicle Packaging as a Novel Therapeutic Mechanism in Pulmonary Hypertension.
  6. Mitochondrial membrane potential acts as a retrograde signal to regulate cell cycle progression.
  7. Mitochondrial degradation: Mitophagy and beyond.
  8. A nucleotide diphosphate kinase mediates tethering between mitochondria prior to fusion.
  9. Alternative to lysosomal degradation: mitochondrial removal via EVs.
  1. Nat Struct Mol Biol. 2023 Sep 11.
    Molecular pathway of mitochondrial preprotein import through the TOM-TIM23 supercomplex.
    Xueyin Zhou, Yuqi Yang, Guopeng Wang, Shanshan Wang, Dongjie Sun, Xiaomin Ou, Yuke Lian, Long Li.
      Over half of mitochondrial proteins are imported from the cytosol via the pre-sequence pathway, controlled by the TOM complex in the outer membrane and the TIM23 complex in the inner membrane. The mechanisms through which proteins are translocated via the TOM and TIM23 complexes remain unclear. Here we report the assembly of the active TOM-TIM23 supercomplex of Saccharomyces cerevisiae with translocating polypeptide substrates. Electron cryo-microscopy analyses reveal that the polypeptide substrates pass the TOM complex through the center of a Tom40 subunit, interacting with a glutamine-rich region. Structural and biochemical analyses show that the TIM23 complex contains a heterotrimer of the subunits Tim23, Tim17 and Mgr2. The polypeptide substrates are shielded from lipids by Mgr2 and Tim17, which creates a translocation pathway characterized by a negatively charged entrance and a central hydrophobic region. These findings reveal an unexpected pre-sequence pathway through the TOM-TIM23 supercomplex spanning the double membranes of mitochondria.
    DOI:  https://doi.org/10.1038/s41594-023-01103-7
  2. Cell Rep. 2023 Sep 06. pii: S2211-1247(23)01092-6. [Epub ahead of print] 113081
    The heat shock protein Hsp27 controls mitochondrial function by modulating ceramide generation.
    Rowan A Boyd, Saurav Majumder, Johnny Stiban, Grace Mavodza, Alexandra J Straus, Sachin K Kempelingaiah, Varun Reddy, Yusuf A Hannun, Lina M Obeid, Can E Senkal.
      Sphingolipids have key functions in membrane structure and cellular signaling. Ceramide is the central molecule of the sphingolipid metabolism and is generated by ceramide synthases (CerS) in the de novo pathway. Despite their critical function, mechanisms regulating CerS remain largely unknown. Using an unbiased proteomics approach, we find that the small heat shock protein 27 (Hsp27) interacts specifically with CerS1 but not other CerS. Functionally, our data show that Hsp27 acts as an endogenous inhibitor of CerS1. Wild-type Hsp27, but not a mutant deficient in CerS1 binding, inhibits CerS1 activity. Additionally, silencing of Hsp27 enhances CerS1-generated ceramide accumulation in cells. Moreover, phosphorylation of Hsp27 modulates Hsp27-CerS1 interaction and CerS1 activity in acute stress-response conditions. Biologically, we show that Hsp27 knockdown impedes mitochondrial function and induces lethal mitophagy in a CerS1-dependent manner. Overall, we identify an important mode of CerS1 regulation and CerS1-mediated mitophagy through protein-protein interaction with Hsp27.
    Keywords:  C18-ceramide; CP: Molecular biology; CerS1; Hsp27; ceramide; ceramide synthase; mitophagy; sphingolipids
    DOI:  https://doi.org/10.1016/j.celrep.2023.113081
  3. Cell Rep. 2023 Sep 12. pii: S2211-1247(23)01044-6. [Epub ahead of print]42(9): 113033
    A STAT3 protein complex required for mitochondrial mRNA stability and cancer.
    C Dilanka Fernando, W Samantha N Jayasekara, Chaitanya Inampudi, Maija R J Kohonen-Corish, Wendy A Cooper, Traude H Beilharz, Tracy M Josephs, Daniel J Garama, Daniel J Gough.
      Signal transducer and activator of transcription 3 (STAT3) is a potent transcription factor necessary for life whose activity is corrupted in diverse diseases, including cancer. STAT3 biology was presumed to be entirely dependent on its activity as a transcription factor until the discovery of a mitochondrial pool of STAT3, which is necessary for normal tissue function and tumorigenesis. However, the mechanism of this mitochondrial activity remained elusive. This study uses immunoprecipitation and mass spectrometry to identify a complex containing STAT3, leucine-rich pentatricopeptide repeat containing (LRPPRC), and SRA stem-loop-interacting RNA-binding protein (SLIRP) that is required for the stability of mature mitochondrially encoded mRNAs and transport to the mitochondrial ribosome. Moreover, we show that this complex is enriched in patients with lung adenocarcinoma and that its deletion inhibits the growth of lung cancer in vivo, providing therapeutic opportunities through the specific targeting of the mitochondrial activity of STAT3.
    Keywords:  CP: Cancer; CP: Molecular biology; LRPPRC; SLIRP; STAT3; lung adenocarcinoma; mRNA stability; mitochondria
    DOI:  https://doi.org/10.1016/j.celrep.2023.113033
  4. Dev Cell. 2023 Sep 07. pii: S1534-5807(23)00435-5. [Epub ahead of print]
    Mitochondrial GTP metabolism controls reproductive aging in C. elegans.
    Yi-Tang Lee, Marzia Savini, Tao Chen, Jin Yang, Qian Zhao, Lang Ding, Shihong Max Gao, Mumine Senturk, Jessica N Sowa, Jue D Wang, Meng C Wang.
      Healthy mitochondria are critical for reproduction. During aging, both reproductive fitness and mitochondrial homeostasis decline. Mitochondrial metabolism and dynamics are key factors in supporting mitochondrial homeostasis. However, how they are coupled to control reproductive health remains unclear. We report that mitochondrial GTP (mtGTP) metabolism acts through mitochondrial dynamics factors to regulate reproductive aging. We discovered that germline-only inactivation of GTP- but not ATP-specific succinyl-CoA synthetase (SCS) promotes reproductive longevity in Caenorhabditis elegans. We further identified an age-associated increase in mitochondrial clustering surrounding oocyte nuclei, which is attenuated by GTP-specific SCS inactivation. Germline-only induction of mitochondrial fission factors sufficiently promotes mitochondrial dispersion and reproductive longevity. Moreover, we discovered that bacterial inputs affect mtGTP levels and dynamics factors to modulate reproductive aging. These results demonstrate the significance of mtGTP metabolism in regulating oocyte mitochondrial homeostasis and reproductive longevity and identify mitochondrial fission induction as an effective strategy to improve reproductive health.
    Keywords:  GTP metabolism; bacteria-host interaction; gene-environment interaction; mitochondrial distribution; mitochondrial dynamics; oocyte quality control; reproductive aging; succinyl-CoA synthetase; vitamin B12
    DOI:  https://doi.org/10.1016/j.devcel.2023.08.019
  5. Am J Respir Cell Mol Biol. 2023 Sep 15.
    Mitochondria Derived Vesicle Packaging as a Novel Therapeutic Mechanism in Pulmonary Hypertension.
    Qiang Zhao, Zhixue Liu, Ping Song, Zuyi Yuan, Ming-Hui Zou.
      Increasing evidence suggests that mitochondrial dysfunction in pulmonary endothelial cells (ECs) plays a causative role in the initiation and progression of pulmonary hypertension (PH); how mitochondria become dysfunctional in PH remains elusive. Mitochondria-derived vesicles (MDVs) are small subcellular vesicles that excise from mitochondria. Whether or not MDVs deregulation causes mitochondrial dysfunction in PH is unknown. This aim of this study was to determine MDVs regulation in ECs and to elucidate how MDVs deregulation in ECs leads to PH. MDVs formation and mitochondrial morphology/dynamics were examined in ECs of the EC-specific-Liver kinase B1 (LKB1) knock out mice (LKB1ec-/-), in monocrotaline (MCT)-induced PH rats, and in lungs of patients with PH. Pulmonary ECs of PH patients and hypoxia-treated pulmonary ECs exhibited increased mitochondrial fragmentation and disorganized mitochondrial ultrastructure characterized by electron lucent-swelling matrix compartments and concentric layering of cristae network, along with defective MDVs shedding. MDVs actively regulated mitochondrial membrane dynamics and mitochondrial ultrastructure via its removing mitofission-related cargoes. The shedding of MDVs from parental mitochondria required LKB1-mediated mitochondrial recruitment of Rab9 GTPase. LKB1ec-/- mice spontaneously developed PH with decreased mitochondrial pools of Rab9 GTPase, defective MDVs shedding, and disequilibrium of mitochondrial fusion-fission cycle in pulmonary ECs. Aerosol intra-tracheal delivery of adeno-associated virus LKB1 reversed PH, along with improved MDVs shedding and mitochondrial functions in rats in vivo. We conclude that LKB1 regulates MDVs shedding and mitochondrial dynamics in pulmonary ECs by enhancing mitochondrial recruitment of Rab9 GTPase. Defect of LKB1-mediated MDVs shedding from parental mitochondria instigates ECs dysfunction and PH.
    Keywords:  Pulmonary hypertension , Endothelial dysfunction , Mitochondria derived vesicles , Liver kinase B1
    DOI:  https://doi.org/10.1165/rcmb.2023-0010OC
  6. Life Sci Alliance. 2023 Dec;pii: e202302091. [Epub ahead of print]6(12):
    Mitochondrial membrane potential acts as a retrograde signal to regulate cell cycle progression.
    Choco Michael Gorospe, Gustavo Carvalho, Alicia Herrera Curbelo, Lisa Marchhart, Isabela C Mendes, Katarzyna Niedźwiecka, Paulina H Wanrooij.
      Mitochondria are central to numerous metabolic pathways whereby mitochondrial dysfunction has a profound impact and can manifest in disease. The consequences of mitochondrial dysfunction can be ameliorated by adaptive responses that rely on crosstalk from the mitochondria to the rest of the cell. Such mito-cellular signalling slows cell cycle progression in mitochondrial DNA-deficient (ρ0) Saccharomyces cerevisiae cells, but the initial trigger of the response has not been thoroughly studied. Here, we show that decreased mitochondrial membrane potential (ΔΨm) acts as the initial signal of mitochondrial stress that delays G1-to-S phase transition in both ρ0 and control cells containing mtDNA. Accordingly, experimentally increasing ΔΨm was sufficient to restore timely cell cycle progression in ρ0 cells. In contrast, cellular levels of oxidative stress did not correlate with the G1-to-S delay. Restored G1-to-S transition in ρ0 cells with a recovered ΔΨm is likely attributable to larger cell size, whereas the timing of G1/S transcription remained delayed. The identification of ΔΨm as a regulator of cell cycle progression may have implications for disease states involving mitochondrial dysfunction.
    DOI:  https://doi.org/10.26508/lsa.202302091
  7. Mol Cell. 2023 Sep 07. pii: S1097-2765(23)00656-1. [Epub ahead of print]
    Mitochondrial degradation: Mitophagy and beyond.
    Louise Uoselis, Thanh Ngoc Nguyen, Michael Lazarou.
      Mitochondria are central hubs of cellular metabolism that also play key roles in signaling and disease. It is therefore fundamentally important that mitochondrial quality and activity are tightly regulated. Mitochondrial degradation pathways contribute to quality control of mitochondrial networks and can also regulate the metabolic profile of mitochondria to ensure cellular homeostasis. Here, we cover the many and varied ways in which cells degrade or remove their unwanted mitochondria, ranging from mitophagy to mitochondrial extrusion. The molecular signals driving these varied pathways are discussed, including the cellular and physiological contexts under which the different degradation pathways are engaged.
    Keywords:  MDV; PINK1; Parkin; degradation; mitochondria; mitochondrial quality control; mitophagy; proteasome; selective autophagy; ubiquitin
    DOI:  https://doi.org/10.1016/j.molcel.2023.08.021
  8. J Cell Biol. 2023 Oct 02. pii: e202309037. [Epub ahead of print]222(10):
    A nucleotide diphosphate kinase mediates tethering between mitochondria prior to fusion.
    Arisa Ikeda, Miho Iijima, Hiromi Sesaki.
      Mitochondrial fusion plays an important role in both their structure and function. In this issue, Su et al. (2023. J. Cell Biol.https://doi.org/10.1083/jcb.202301091) report that a nucleoside diphosphate kinase, NME3, facilitates mitochondrial tethering prior to fusion through its direct membrane-binding and hexamerization but not its kinase activity.
    DOI:  https://doi.org/10.1083/jcb.202309037
  9. Nat Rev Mol Cell Biol. 2023 Sep 11.
    Alternative to lysosomal degradation: mitochondrial removal via EVs.
    Paulina Strzyz.
      
    DOI:  https://doi.org/10.1038/s41580-023-00660-5
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