bims-mitlys Biomed News
on Mitochondria and Lysosomes
Issue of 2021–08–29
ten papers selected by
Nicoletta Plotegher, University of Padova
  1. The Loss of Mitochondrial Quality Control in Diabetic Kidney Disease.
  2. The Expanding Role of Mitochondria, Autophagy and Lipophagy in Steroidogenesis.
  3. GRP78 Overexpression Triggers PINK1-IP3R-Mediated Neuroprotective Mitophagy.
  4. C5orf51 is a component of the MON1-CCZ1 complex and controls RAB7A localization and stability during mitophagy.
  5. Neuronal organelle contacts.
  6. Mitophagy Regulates Neurodegenerative Diseases.
  7. Fenpropathrin induces degeneration of dopaminergic neurons via disruption of the mitochondrial quality control system.
  8. PINK1 antagonize intracerebral hemorrhage by promoting mitochondrial autophagy.
  9. Loosening ER-Mitochondria Coupling by the Expression of the Presenilin 2 Loop Domain.
  10. The Interplay between Autophagy and NLRP3 Inflammasome in Ischemia/Reperfusion Injury.
  1. Front Cell Dev Biol. 2021 ;9 706832
    The Loss of Mitochondrial Quality Control in Diabetic Kidney Disease.
    Wenni Dai, Hengcheng Lu, Yinyin Chen, Danyi Yang, Lin Sun, Liyu He.
      Diabetic kidney disease (DKD) is the predominant complication of diabetes mellitus (DM) and the leading cause of chronic kidney disease and end-stage renal disease worldwide, which are major risk factors for death. The pathogenesis of DKD is very complicated, including inflammation, autophagy impairment, oxidative stress, and so on. Recently, accumulating evidence suggests that the loss of mitochondrial quality control exerts critical roles in the progression of DKD. Mitochondria are essential for eukaryotic cell viability but are extremely vulnerable to damage. The mechanisms of mitochondrial quality control act at the molecular level and the organelle level, including mitochondrial dynamics (fusion and fission), mitophagy, mitochondrial biogenesis, and mitochondrial protein quality control. In this review, we summarize current knowledge of the role of disturbances in mitochondrial quality control in the pathogenesis of DKD and provide potential insights to explore how to delay the onset and development of DKD.
    Keywords:  diabetic kidney disease; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial protein quality control; mitochondrial quality control; mitophagy; oxidative stress
    DOI:  https://doi.org/10.3389/fcell.2021.706832
  2. Cells. 2021 Jul 22. pii: 1851. [Epub ahead of print]10(8):
    The Expanding Role of Mitochondria, Autophagy and Lipophagy in Steroidogenesis.
    Geetika Bassi, Simarjit Kaur Sidhu, Suresh Mishra.
      The fundamental framework of steroidogenesis is similar across steroidogenic cells, especially in initial mitochondrial steps. For instance, the START domain containing protein-mediated cholesterol transport to the mitochondria, and its conversion to pregnenolone by the enzyme P450scc, is conserved across steroidogenic cells. The enzyme P450scc localizes to the inner mitochondrial membrane, which makes the mitochondria essential for steroidogenesis. Despite this commonality, mitochondrial structure, number, and dynamics vary substantially between different steroidogenic cell types, indicating implications beyond pregnenolone biosynthesis. This review aims to focus on the growing roles of mitochondria, autophagy and lipophagy in cholesterol uptake, trafficking and homeostasis in steroidogenic cells and consequently in steroidogenesis. We will focus on these aspects in the context of the physiological need for different steroid hormones and cell-intrinsic inherent features in different steroidogenic cell types beyond mitochondria as a mere site for the beginning of steroidogenesis. The overall goal is to provide an authentic and comprehensive review on the expanding role of steroidogenic cell-intrinsic processes in cholesterol homeostasis and steroidogenesis, and to bring attention to the scientific community working in this field on these promising advancements. Moreover, we will discuss a novel mitochondrial player, prohibitin, and its potential role in steroidogenic mitochondria and cells, and consequently, in steroidogenesis.
    Keywords:  adrenal gland; autophagy; cholesterol; lipophagy; mitochondrial; ovary; placenta; testis
    DOI:  https://doi.org/10.3390/cells10081851
  3. Biomedicines. 2021 Aug 18. pii: 1039. [Epub ahead of print]9(8):
    GRP78 Overexpression Triggers PINK1-IP3R-Mediated Neuroprotective Mitophagy.
    Tatiana Leiva-Rodríguez, David Romeo-Guitart, Mireia Herrando-Grabulosa, Pau Muñoz-Guardiola, Miriam Polo, Celia Bañuls, Valerie Petegnief, Assumpció Bosch, Jose Miguel Lizcano, Nadezda Apostolova, Joaquim Forés, Caty Casas.
      An experimental model of spinal root avulsion (RA) is useful to study causal molecular programs that drive retrograde neurodegeneration after neuron-target disconnection. This neurodegenerative process shares common characteristics with neuronal disease-related processes such as the presence of endoplasmic reticulum (ER) stress and autophagy flux blockage. We previously found that the overexpression of GRP78 promoted motoneuronal neuroprotection after RA. After that, we aimed to unravel the underlying mechanism by carrying out a comparative unbiased proteomic analysis and pharmacological and genetic interventions. Unexpectedly, mitochondrial factors turned out to be most altered when GRP78 was overexpressed, and the abundance of engulfed mitochondria, a hallmark of mitophagy, was also observed by electronic microscopy in RA-injured motoneurons after GRP78 overexpression. In addition, GRP78 overexpression increased LC3-mitochondria tagging, promoted PINK1 translocation, mitophagy induction, and recovered mitochondrial function in ER-stressed cells. Lastly, we found that GRP78-promoted pro-survival mitophagy was mediated by PINK1 and IP3R in our in vitro model of motoneuronal death. This data indicates a novel relationship between the GRP78 chaperone and mitophagy, opening novel therapeutical options for drug design to achieve neuroprotection.
    Keywords:  GRP78/BiP; mitophagy; motoneurons; neurodegeneration; neuroprotection
    DOI:  https://doi.org/10.3390/biomedicines9081039
  4. Autophagy. 2021 Aug 25. 1-12
    C5orf51 is a component of the MON1-CCZ1 complex and controls RAB7A localization and stability during mitophagy.
    Bing-Ru Yan, Taoyingnan Li, Etienne Coyaud, Estelle M N Laurent, Jonathan St-Germain, Yuhuan Zhou, Peter K Kim, Brian Raught, John H Brumell.
      Depolarized mitochondria can be degraded via mitophagy, a selective form of autophagy. The RAB GTPase RAB7A was recently shown to play a key role in this process. RAB7A regulates late endocytic trafficking under normal growth conditions but is translocated to the mitochondrial surface following depolarization. However, how RAB7A activity is regulated during mitophagy is not understood. Here, using a proximity-dependent biotinylation approach (miniTurbo), we identified C5orf51 as a specific interactor of GDP-locked RAB7A. C5orf51 also interacts with the RAB7A guanine nucleotide exchange factor (GEF) complex members MON1 and CCZ1. In the absence of C5orf51, localization of RAB7A on depolarized mitochondria is compromised and the protein is degraded by the proteasome. Furthermore, depletion of C5orf51 also inhibited ATG9A recruitment to depolarized mitochondria. Together, these results indicate that C5orf51 is a positive regulator of RAB7A in its shuttling between late endosomes and mitochondria to enable mitophagy.Abbreviations: ATG9A: autophagy related 9A; Baf A1: bafilomycin A1; BioID: proximity-dependent biotin identification; CCCP: carbonyl cyanide m-chlorophenylhydrazone; CCZ1: CCZ1 homolog, vacuolar protein trafficking and biogenesis associated; DQ-BSA: dye quenched-bovine serum albumin; FYCO1: FYVE and coiled-coil domain autophagy adaptor 1; GAP: GTPase activating protein; GEF: guanine nucleotide exchange factor; KO: knockout; LRPPRC: leucine rich pentatricopeptide repeat containing; MG132: carbobenzoxy-Leu-Leu-leucinal; MON1: MON1 homolog, secretory trafficking associated; mtDNA: mitochondrial DNA; PINK1: PTEN induced kinase 1; PRKN/PARKIN: parkin RBR E3 ubiquitin protein ligase; RMC1: regulator of MON1-CCZ1; TBC1D15: TBC1 domain family member 15; TBC1D17: TBC1 domain family member 17; TOMM20: translocase of outer mitochondrial membrane 20; WDR91: WD repeat domain 91; WT: wild type.
    Keywords:  Autophagy; C5orf51; RAB7A; guanine nucleotide exchange factor; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2021.1960116
  5. Nat Rev Neurosci. 2021 Aug 25.
    Neuronal organelle contacts.
    Jake Rogers.
      
    DOI:  https://doi.org/10.1038/s41583-021-00520-1
  6. Cells. 2021 Jul 24. pii: 1876. [Epub ahead of print]10(8):
    Mitophagy Regulates Neurodegenerative Diseases.
    Xufeng Cen, Manke Zhang, Mengxin Zhou, Lingzhi Ye, Hongguang Xia.
      Mitochondria play an essential role in supplying energy for the health and survival of neurons. Mitophagy is a metabolic process that removes dysfunctional or redundant mitochondria. This process preserves mitochondrial health. However, defective mitophagy triggers the accumulation of damaged mitochondria, causing major neurodegenerative disorders. This review introduces molecular mechanisms and signaling pathways behind mitophagy regulation. Furthermore, we focus on the recent advances in understanding the potential role of mitophagy in the pathogenesis of major neurodegenerative diseases (Parkinson's, Alzheimer's, Huntington's, etc.) and aging. The findings will help identify the potential interventions of mitophagy regulation and treatment strategies of neurodegenerative diseases.
    Keywords:  Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; mitophagy; neurodegenerative diseases
    DOI:  https://doi.org/10.3390/cells10081876
  7. Cell Death Discov. 2020 Aug 25. 6(1): 78
    Fenpropathrin induces degeneration of dopaminergic neurons via disruption of the mitochondrial quality control system.
    Zhigang Jiao, Yixuan Wu, Shaogang Qu.
      The synthetic pyrethroid derivative, fenpropathrin, is a widely used insecticide. However, a variety of toxic effects in mammals have been reported. In particular, fenpropathrin induces degeneration of dopaminergic neurons and parkinsonism. However, the mechanism of fenpropathrin-induced parkinsonism has remained unknown. In the present study, we investigated the toxic effects and underlying mechanisms of fenpropathrin on perturbing the dopaminergic system both in vivo and in vitro. We found that fenpropathrin induced cellular death of dopaminergic neurons in vivo. Furthermore, fenpropathrin increased the generation of reactive oxygen species, disrupted both mitochondrial function and dynamic networks, impaired synaptic communication, and promoted mitophagy in vitro. In mice, fenpropathrin was administered into the striatum via stereotaxic (ST) injections. ST-injected mice exhibited poor locomotor function at 24 weeks after the first ST injection and the number of tyrosine hydroxylase (TH)-positive cells and level of TH protein in the substantia nigra pars compacta were significantly decreased, as compared to these parameters in vehicle-treated mice. Taken together, our results demonstrate that exposure to fenpropathrin induces a loss of dopaminergic neurons and partially mimics the pathologic features of Parkinson's disease. These findings suggest that fenpropathrin may induce neuronal degeneration via dysregulation of mitochondrial function and the mitochondrial quality control system.
    DOI:  https://doi.org/10.1038/s41420-020-00313-y
  8. Ann Clin Transl Neurol. 2021 Aug 28.
    PINK1 antagonize intracerebral hemorrhage by promoting mitochondrial autophagy.
    Jingchen Li, Xiaoyun Wu, Yanbo He, Song Wu, Erkun Guo, Yan Feng, Jipeng Yang, Jianliang Li.
       BACKGROUND: Intracerebral hemorrhage (ICH) causes neurotransmitter release, oligemia, membrane depolarization, mitochondrial dysfunction, and results in the high rate of mortality and functional disability. Here, we focus on PTEN-induced kinase 1 (PINK1), a mitochondrial-targeted protein kinase, and explore its role in ICH progression.
    METHODS: The qPCR and Western blot were performed to examine the expression of PINK1 in ICH patients and mouse model. PINK1 gain- and loss-of-function mice were used to evaluate their protective role on brain injury and behavioral disorders. Flow cytometry was carried out, mitochondrial membrane potential and reactive oxygen species production were detected to explore the distribution and neuroprotective function of PINK1.
    RESULTS: PINK1 mRNA was upregulated, however, its protein was downregulated in ICH patients. The reduction of PINK1 was mainly happened in microglial cells in ICH model. Overexpression of PINK1 is able to rescue ICH-induced behavioral disorders. PINK1 protects ICH-induced brain injury by promoting mitochondrial autophagy in microglia.
    CONCLUSION: PINK1 possesses a neuroprotective role and antagonizes ICH by promoting mitochondrial autophagy, which may be of value as a therapeutic target for ICH treatment.
    DOI:  https://doi.org/10.1002/acn3.51425
  9. Cells. 2021 Aug 03. pii: 1968. [Epub ahead of print]10(8):
    Loosening ER-Mitochondria Coupling by the Expression of the Presenilin 2 Loop Domain.
    Michela Rossini, Paloma García-Casas, Riccardo Filadi, Paola Pizzo.
      Presenilin 2 (PS2), one of the three proteins in which mutations are linked to familial Alzheimer's disease (FAD), exerts different functions within the cell independently of being part of the γ-secretase complex, thus unrelated to toxic amyloid peptide formation. In particular, its enrichment in endoplasmic reticulum (ER) membrane domains close to mitochondria (i.e., mitochondria-associated membranes, MAM) enables PS2 to modulate multiple processes taking place on these signaling hubs, such as Ca2+ handling and lipid synthesis. Importantly, upregulated MAM function appears to be critical in AD pathogenesis. We previously showed that FAD-PS2 mutants reinforce ER-mitochondria tethering, by interfering with the activity of mitofusin 2, favoring their Ca2+ crosstalk. Here, we deepened the molecular mechanism underlying PS2 activity on ER-mitochondria tethering, identifying its protein loop as an essential domain to mediate the reinforced ER-mitochondria connection in FAD-PS2 models. Moreover, we introduced a novel tool, the PS2 loop domain targeted to the outer mitochondrial membrane, Mit-PS2-LOOP, that is able to counteract the activity of FAD-PS2 on organelle tethering, which possibly helps in recovering the FAD-PS2-associated cellular alterations linked to an increased organelle coupling.
    Keywords:  Alzheimer’s disease; Ca2+ signaling; ER; MAM; Presenilin 2; mitochondria; organelle contacts
    DOI:  https://doi.org/10.3390/cells10081968
  10. Int J Mol Sci. 2021 Aug 16. pii: 8773. [Epub ahead of print]22(16):
    The Interplay between Autophagy and NLRP3 Inflammasome in Ischemia/Reperfusion Injury.
    Shuangyu Lv, Huiyang Liu, Honggang Wang.
      Ischemia/reperfusion (I/R) injury is characterized by a limited blood supply to organs, followed by the restoration of blood flow and reoxygenation. In addition to ischemia, blood flow recovery can also lead to very harmful injury, especially inflammatory injury. Autophagy refers to the transport of cellular materials to the lysosomes for degradation, leading to the conversion of cellular components and offering energy and macromolecular precursors. It can maintain the balance of synthesis, decomposition and reuse of the intracellular components, and participate in many physiological processes and diseases. Inflammasomes are a kind of protein complex. Under physiological and pathological conditions, as the cellular innate immune signal receptors, inflammasomes sense pathogens to trigger an inflammatory response. TheNLRP3 inflammasome is the most deeply studied inflammasome and is composed of NLRP3, the adaptor apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and pro-caspase-1. Its activation triggers the cleavage of pro-interleukin (IL)-1β and pro-IL-18 mediated by caspase-1 and promotes a further inflammatory process. Studies have shown that autophagy and the NLRP3 inflammasome play an important role in the process of I/R injury, but the relevant mechanisms have not been fully explained, especially how the interaction between autophagy and the NLRP3 inflammasome participates in I/R injury, which remains to be further studied. Therefore, we reviewed the recent studies about the interplay between autophagy and the NLRP3 inflammasome in I/R injury and analyzed the mechanisms to provide the theoretical references for further research in the future.
    Keywords:  NLRP3 inflammasome; autophagy; ischemia/reperfusion injury; mitophagy; reactive oxygen species
    DOI:  https://doi.org/10.3390/ijms22168773
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