bims-mitlys Biomed News
on Mitochondria and Lysosomes
Issue of 2021‒11‒21
six papers selected by
Nicoletta Plotegher
University of Padova
  1. Beyond mitophagy: mitochondrial-derived vesicles can get the job done!
  2. AMBRA1 regulates mitophagy by interacting with ATAD3A and promoting PINK1 stability.
  3. ATG2 and VPS13 proteins: Molecular highways transporting lipids to drive membrane expansion and organelle communication.
  4. Hello from the other side: Membrane contact of lipid droplets with other organelles and subsequent functional implications.
  5. The neuroprotective effect of increased PINK1 expression following glutamate excitotoxicity in neuronal cells.
  6. Mitophagy Mediates Metabolic Reprogramming of Induced Pluripotent Stem Cells Undergoing Endothelial Differentiation.
  1. Autophagy. 2021 Nov 15. 1-3
    Beyond mitophagy: mitochondrial-derived vesicles can get the job done!
    Payel Mondal, Christina Towers.
      Mitochondria are critical organelles that maintain cellular metabolism and overall function. The catabolic pathway of autophagy plays a central role in recycling damaged mitochondria. Although the autophagy pathway is indispensable for some cancer cell survival, our latest study shows that rare autophagy-dependent cancer cells can adapt to loss of this core pathway. In the process, the autophagy-deficient cells acquire unique dependencies on alternate forms of mitochondrial homeostasis. These rare autophagy-deficient clones circumvent the lack of canonical autophagy by increasing mitochondrial dynamics and by recycling damaged mitochondria via mitochondrial-derived vesicles (MDVs). These studies are the first to implicate MDVs in cancer cell metabolism although many unanswered questions remain about this non-canonical pathway.
    Keywords:  Cancer; mitochondrial fusion; mitochondrial-derived vesicles; mitophagy; non-canonical autophagy
    DOI:  https://doi.org/10.1080/15548627.2021.1999562
  2. Autophagy. 2021 Nov 19. 1-11
    AMBRA1 regulates mitophagy by interacting with ATAD3A and promoting PINK1 stability.
    Martina Di Rienzo, Alessandra Romagnoli, Fabiola Ciccosanti, Giulia Refolo, Veronica Consalvi, Giuseppe Arena, Enza Maria Valente, Mauro Piacentini, Gian Maria Fimia.
      PINK1 accumulation at the outer mitochondrial membrane (OMM) is a key event required to signal depolarized mitochondria to the autophagy machinery. How this early step is, in turn, modulated by autophagy proteins remains less characterized. Here, we show that, upon mitochondrial depolarization, the proautophagic protein AMBRA1 is recruited to the OMM and interacts with PINK1 and ATAD3A, a transmembrane protein that mediates mitochondrial import and degradation of PINK1. Downregulation of AMBRA1 expression results in reduced levels of PINK1 due to its enhanced degradation by the mitochondrial protease LONP1, which leads to a decrease in PINK1-mediated ubiquitin phosphorylation and mitochondrial PRKN/PARKIN recruitment. Notably, ATAD3A silencing rescues defective PINK1 accumulation in AMBRA1-deficient cells upon mitochondrial damage. Overall, our findings underline an upstream contribution of AMBRA1 in the control of PINK1-PRKN mitophagy by interacting with ATAD3A and promoting PINK1 stability. This novel regulatory element may account for changes of PINK1 levels in neuropathological conditions.
    Keywords:  Autophagy; LONP1; PRKN/PARKIN; TOMM complex; ubiquitin phosphorylation
    DOI:  https://doi.org/10.1080/15548627.2021.1997052
  3. FEBS J. 2021 Nov 16.
    ATG2 and VPS13 proteins: Molecular highways transporting lipids to drive membrane expansion and organelle communication.
    David G McEwan, Kevin Ryan.
      Communication between organelles is an essential process that helps maintain cellular homeostasis and organelle contact sites have emerged recently as crucial mediators of this communication. The emergence of a class of molecular bridges that span the inter-organelle gaps has now been shown to direct the flow of lipid traffic from one lipid bilayer to another. One of the keys components of these molecular bridges is the presence of an N-terminal Chorein/VPS13 domain. This is an evolutionarily conserved domain present in multiple proteins within the endocytic and autophagy trafficking pathways. Herein, we discuss the current state-of-the-art of this class of proteins, focusing on the role of these lipid transporters in the autophagy and endocytic pathways. We discuss the recent biochemical and structural advances that have highlighted the essential role Chorein-N domain containing ATG2 proteins play in driving the formation of the autophagosome and how lipids are transported from the endoplasmic reticulum to the growing phagophore. We also consider the VPS13 proteins, their role in organelle contacts and the endocytic pathway and highlight how disease-causing mutations disrupt these contact sites. Finally, we open the door to discuss other Chorein_N domain containing proteins, for instance UHRF1BP1/1L, their role in disease and look towards prokaryote examples of Chorein_N-like domains. Taken together, recent advances have highlighted an exciting opportunity to delve deeper into inter-organelle communication and understand how lipids are transported between membrane bi-layers and how this process is disrupted in multiple diseases.
    Keywords:  ATG2; Autophagy; Chorein; Lipid transfer; UHRF1BP1; VPS13; endosome; organelle contacts
    DOI:  https://doi.org/10.1111/febs.16280
  4. Prog Lipid Res. 2021 Nov 15. pii: S0163-7827(21)00057-6. [Epub ahead of print] 101141
    Hello from the other side: Membrane contact of lipid droplets with other organelles and subsequent functional implications.
    Rebekah Rakotonirina-Ricquebourg, Vítor Costa, Vitor Teixeira.
      Lipid droplets (LDs) are ubiquitous organelles that play crucial roles in response to physiological and environmental cues. The identification of several neutral lipid synthesizing and regulatory protein complexes have propelled significant advance on the mechanisms of LD biogenesis in the endoplasmic reticulum (ER). Increasing evidence suggests that distinct proteins and regulatory factors, which localize to membrane contact sites (MCS), are involved not only in interorganellar lipid exchange and transport, but also function in other important cellular processes, including autophagy, mitochondrial dynamics and inheritance, ion signaling and inter-regulation of these MCS. More and more tethers and molecular determinants are associated to MCS and to a diversity of cellular and pathophysiological processes, demonstrating the dynamics and importance of these junctions in health and disease. The conjugation of lipids with proteins in supramolecular complexes is known to be paramount for many biological processes, namely membrane biosynthesis, cell homeostasis, regulation of organelle division and biogenesis, and cell growth. Ultimately, this physical organization allows the contact sites to function as crucial metabolic hubs that control the occurrence of chemical reactions. This leads to biochemical and metabolite compartmentalization for the purposes of energetic efficiency and cellular homeostasis. In this review, we will focus on the structural and functional aspects of LD-organelle interactions and how they ensure signaling exchange and metabolites transfer between organelles.
    Keywords:  Interorganellar communication; Lipid droplet; Membrane biogenesis; Membrane contact sites; Metabolism; Molecular tether
    DOI:  https://doi.org/10.1016/j.plipres.2021.101141
  5. Neuroscience. 2021 Nov 16. pii: S0306-4522(21)00579-0. [Epub ahead of print]
    The neuroprotective effect of increased PINK1 expression following glutamate excitotoxicity in neuronal cells.
    Ya-Nan Dou, Xiuquan Wu, Xiaowei Fei, Zhou Fei.
      Ischemic injury in patients with stroke often leads to neuronal damage and mitochondrial dysfunction. Neuronal injury caused by ischemia can be partly attributed to glutamate (L-Glu) excitotoxicity. Previous studies have shown that PTEN-induced kinase 1 (PINK1) plays a neuroprotective role in ischemic brain injury by regulating mitochondrial integrity and function. However, there are few reports on the expression of PINK1 in L-Glu excitotoxicity models, its effect on neuronal survival, and whether PINK1 plays a protective role in stroke by regulating mitophagy. In the present study, different concentrations of L-Glu inhibited the viability of neurons. After L-Glu treatment at different times, the mRNA level, protein level, and cellular fluorescence intensity of PINK1 first increased and then decreased. Compared with normal cells, cells with low PINK1 expression enhanced the inhibitory effect of L-Glu on neuronal activity, while those with high PINK1 expression showed a protective effect on neurons by alleviating mitochondrial membrane potential loss. In addition, RAP (an autophagy activator) could increase the co-localization of the mitophagy-related proteins light chain 3 (LC3) and Tom20, whereas 3-MA (an autophagy inhibitor) exerted the opposite effect. Finally, we found that L-Glu could induce the expression of PINK1/Parkin/ LC3 in neurons at both mRNA and protein levels, while RAP could further increase their expression, and 3-MA decreased their expression. Taken together, PINK1 protects against L-Glu-induced neuronal injury by protecting mitochondrial function, and the potential protective mechanism may be closely related to the enhancement of mitophagy mediated by the PINK1/Parkin signaling pathway.
    Keywords:  Glutamate excitotoxicity; Ischemic stroke; LC3; Mitophagy; PINK1; Parkin
    DOI:  https://doi.org/10.1016/j.neuroscience.2021.11.020
  6. J Biol Chem. 2021 Nov 13. pii: S0021-9258(21)01217-5. [Epub ahead of print] 101410
    Mitophagy Mediates Metabolic Reprogramming of Induced Pluripotent Stem Cells Undergoing Endothelial Differentiation.
    Sarah Krantz, Young-Mee Kim, Shubhi Srivastava, Joseph W Leasure, Peter T Toth, Glenn Marsboom, Jalees Rehman.
      Pluripotent stem cells are known to shift their mitochondrial metabolism upon differentiation, but the mechanisms underlying such metabolic rewiring are not fully understood. We hypothesized that during differentiation of human induced pluripotent stem cells (hiPSCs), mitochondria undergo mitophagy and are then replenished by the biogenesis of new mitochondria adapted to the metabolic needs of the differentiated cell. To evaluate mitophagy during iPSC differentiation, we performed live cell imaging of mitochondria and lysosomes in hiPSCs differentiating into vascular endothelial cells using confocal microscopy. We observed a burst of mitophagy during the initial phases of hiPSC differentiation into the endothelial lineage, followed by subsequent mitochondrial biogenesis as assessed by the mitochondrial biogenesis biosensor MitoTimer. Furthermore, hiPSCs undergoing differentiation showed greater mitochondrial oxidation of fatty acids and an increase in ATP levels as assessed by an ATP biosensor. We also found that during mitophagy, the mitochondrial phosphatase PGAM5 is cleaved in hiPSC-derived endothelial progenitor cells and in turn activates β-catenin-mediated transcription of the transcriptional co-activator PGC-1α, which upregulates mitochondrial biogenesis. These data suggest that mitophagy itself initiates the increase in mitochondrial biogenesis and oxidative metabolism through transcriptional changes during endothelial cell differentiation. In summary, these findings reveal a mitophagy-mediated mechanism for metabolic rewiring and maturation of differentiating cells via the β-catenin signaling pathway. We propose that such mitochondrial-nuclear crosstalk during hiPSC differentiation could be leveraged to enhance the metabolic maturation of differentiated cells.
    Keywords:  cell differentiation; induced pluripotent stem cells; mitochondrial metabolism; mitophagy; β-catenin
    DOI:  https://doi.org/10.1016/j.jbc.2021.101410
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