bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2020–07–26
fourteen papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. PDZD8 interacts with Protrudin and Rab7 at ER-late endosome membrane contact sites associated with mitochondria.
  2. Mitochondria-lysosome contacts regulate mitochondrial Ca2+ dynamics via lysosomal TRPML1.
  3. Lipopolysaccharide promotes Drp1-dependent mitochondrial fission and associated inflammatory responses in macrophages.
  4. Mitochondrial dynamics quantitatively revealed by STED nanoscopy with an enhanced squaraine variant probe.
  5. The GDP-Bound State of Mitochondrial Mfn1 Induces Membrane Adhesion of Apposing Lipid Vesicles through a Cooperative Binding Mechanism.
  6. Lactate: the ugly duckling of energy metabolism.
  7. Disruption of endoplasmic reticulum-mitochondria tethering proteins in post-mortem Alzheimer's disease brain.
  8. Last step in the path of LDL cholesterol from lysosome to plasma membrane to ER is governed by phosphatidylserine.
  9. The roles of cytosolic and intramitochondrial Ca2+ and the mitochondrial Ca2+-uniporter (MCU) in the stimulation of mammalian oxidative phosphorylation.
  10. The Multifaceted Pyruvate Metabolism: Role of the Mitochondrial Pyruvate Carrier.
  11. Hematopoietic Stem Cell Metabolism during Development and Aging.
  12. Altered mitochondrial dynamics and function in APOE4-expressing astrocytes.
  13. Pharmacologic IRE1/XBP1s activation confers targeted ER proteostasis reprogramming.
  14. Mitochondrial Oxidation of Ubiquinol Is Required for Tumorigenesis.
  1. Nat Commun. 2020 Jul 20. 11(1): 3645
    PDZD8 interacts with Protrudin and Rab7 at ER-late endosome membrane contact sites associated with mitochondria.
    Yael Elbaz-Alon, Yuting Guo, Nadav Segev, Michal Harel, Daniel E Quinnell, Tamar Geiger, Ori Avinoam, Dong Li, Jodi Nunnari.
      Endosomes are compositionally dynamic organelles that regulate signaling, nutrient status and organelle quality by specifying whether material entering the cells will be shuttled back to the cell surface or degraded by the lysosome. Recently, membrane contact sites (MCSs) between the endoplasmic reticulum (ER) and endosomes have emerged as important players in endosomal protein sorting, dynamics and motility. Here, we show that PDZD8, a Synaptotagmin-like Mitochondrial lipid-binding Proteins (SMP) domain-containing ER transmembrane protein, utilizes distinct domains to interact with Rab7-GTP and the ER transmembrane protein Protrudin and together these components localize to an ER-late endosome MCS. At these ER-late endosome MCSs, mitochondria are also recruited to form a three-way contact. Thus, our data indicate that PDZD8 is a shared component of two distinct MCSs and suggest a role for SMP-mediated lipid transport in the regulation of endosome function.
    DOI:  https://doi.org/10.1038/s41467-020-17451-7
  2. Proc Natl Acad Sci U S A. 2020 Jul 23. pii: 202003236. [Epub ahead of print]
    Mitochondria-lysosome contacts regulate mitochondrial Ca2+ dynamics via lysosomal TRPML1.
    Wesley Peng, Yvette C Wong, Dimitri Krainc.
      Mitochondria and lysosomes are critical for cellular homeostasis, and dysfunction of both organelles has been implicated in numerous diseases. Recently, interorganelle contacts between mitochondria and lysosomes were identified and found to regulate mitochondrial dynamics. However, whether mitochondria-lysosome contacts serve additional functions by facilitating the direct transfer of metabolites or ions between the two organelles has not been elucidated. Here, using high spatial and temporal resolution live-cell microscopy, we identified a role for mitochondria-lysosome contacts in regulating mitochondrial calcium dynamics through the lysosomal calcium efflux channel, transient receptor potential mucolipin 1 (TRPML1). Lysosomal calcium release by TRPML1 promotes calcium transfer to mitochondria, which was mediated by tethering of mitochondria-lysosome contact sites. Moreover, mitochondrial calcium uptake at mitochondria-lysosome contact sites was modulated by the outer and inner mitochondrial membrane channels, voltage-dependent anion channel 1 and the mitochondrial calcium uniporter, respectively. Since loss of TRPML1 function results in the lysosomal storage disorder mucolipidosis type IV (MLIV), we examined MLIV patient fibroblasts and found both altered mitochondria-lysosome contact dynamics and defective contact-dependent mitochondrial calcium uptake. Thus, our work highlights mitochondria-lysosome contacts as key contributors to interorganelle calcium dynamics and their potential role in the pathophysiology of disorders characterized by dysfunctional mitochondria or lysosomes.
    Keywords:  TRPML1; calcium; lysosomal storage disorder; mitochondria–lysosome contacts; interorganelle membrane contact sites
    DOI:  https://doi.org/10.1073/pnas.2003236117
  3. Immunol Cell Biol. 2020 Jul 20.
    Lipopolysaccharide promotes Drp1-dependent mitochondrial fission and associated inflammatory responses in macrophages.
    Ronan Kapetanovic, Syeda Farhana Afroz, Divya Ramnath, Grace Mep Lawrence, Takashi Okada, James Eb Curson, Jost de Bruin, David P Fairlie, Kate Schroder, Justin C St John, Antje Blumenthal, Matthew J Sweet.
      Mitochondria have a multitude of functions, including energy generation and cell signaling. Recent evidence suggests that mitochondrial dynamics (i.e. the balance between mitochondrial fission and fusion) also regulate immune functions. Here, we reveal that lipopolysaccharide (LPS) stimulation increases mitochondrial numbers in mouse bone marrow-derived macrophages (BMMs) and human monocyte-derived macrophages. In BMMs, this response requires Toll-like receptor 4 (Tlr4) and the TLR adaptor protein myeloid differentiation primary response 88 (MyD88) but is independent of mitochondrial biogenesis. Consistent with this phenomenon being a consequence of mitochondrial fission, the dynamin-related protein 1 (Drp1) GTPase that promotes mitochondrial fission is enriched on mitochondria in LPS-activated macrophages and is required for the LPS-mediated increase in mitochondrial numbers in both BMMs and mouse embryonic fibroblasts. Pharmacological agents that skew toward mitochondrial fusion also abrogated this response. LPS triggered acute Drp1 phosphorylation at serine 635 (S635), followed by sustained Drp1 dephosphorylation at serine 656 (S656), in BMMs. LPS-induced S656 dephosphorylation was abrogated in MyD88-deficient BMMs, suggesting that this post-translational modification is particularly important for Tlr4-inducible fission. Pharmacological or genetic targeting of Tlr4-inducible fission had selective effects on inflammatory mediator production, with LPS-inducible mitochondrial fission promoting the expression and/or secretion of a subset of inflammatory mediators in BMMs and mouse embryonic fibroblasts. Thus, triggering of Tlr4 results in MyD88-dependent activation of Drp1, leading to inducible mitochondrial fission and subsequent inflammatory responses in macrophages.
    Keywords:  Dynamin-related protein 1; Toll-like receptor; lipopolysaccharide; macrophage; mitochondrial dynamics; mitochondrial fission
    DOI:  https://doi.org/10.1111/imcb.12363
  4. Nat Commun. 2020 Jul 24. 11(1): 3699
    Mitochondrial dynamics quantitatively revealed by STED nanoscopy with an enhanced squaraine variant probe.
    Xusan Yang, Zhigang Yang, Zhaoyang Wu, Ying He, Chunyan Shan, Peiyuan Chai, Chenshuo Ma, Mi Tian, Junlin Teng, Dayong Jin, Wei Yan, Pintu Das, Junle Qu, Peng Xi.
      Mitochondria play a critical role in generating energy to support the entire lifecycle of biological cells, yet it is still unclear how their morphological structures evolve to regulate their functionality. Conventional fluorescence microscopy can only provide ~300 nm resolution, which is insufficient to visualize mitochondrial cristae. Here, we developed an enhanced squaraine variant dye (MitoESq-635) to study the dynamic structures of mitochondrial cristae in live cells with a superresolution technique. The low saturation intensity and high photostability of MitoESq-635 make it ideal for long-term, high-resolution (stimulated emission depletion) STED nanoscopy. We performed time-lapse imaging of the mitochondrial inner membrane over 50 min (3.9 s per frame, with 71.5 s dark recovery) in living HeLa cells with a resolution of 35.2 nm. The forms of the cristae during mitochondrial fusion and fission can be clearly observed. Our study demonstrates the emerging capability of optical STED nanoscopy to investigate intracellular physiological processes with nanoscale resolution for an extended period of time.
    DOI:  https://doi.org/10.1038/s41467-020-17546-1
  5. Biomolecules. 2020 Jul 21. pii: E1085. [Epub ahead of print]10(7):
    The GDP-Bound State of Mitochondrial Mfn1 Induces Membrane Adhesion of Apposing Lipid Vesicles through a Cooperative Binding Mechanism.
    Andrés Tolosa-Díaz, Víctor G Almendro-Vedia, Paolo Natale, Iván López-Montero.
      Mitochondria are double-membrane organelles that continuously undergo fission and fusion. Outer mitochondrial membrane fusion is mediated by the membrane proteins mitofusin 1 (Mfn1) and mitofusin 2 (Mfn2), carrying a GTP hydrolyzing domain (GTPase) and two coiled-coil repeats. The detailed mechanism on how the GTP hydrolysis allows Mfns to approach adjacent membranes into proximity and promote their fusion is currently under debate. Using model membranes built up as giant unilamellar vesicles (GUVs), we show here that Mfn1 promotes membrane adhesion of apposing lipid vesicles. The adhesion forces were sustained by the GDP-bound state of Mfn1 after GTP hydrolysis. In contrast, the incubation with the GDP:AlF 4 - , which mimics the GTP transition state, did not induce membrane adhesion. Due to the flexible nature of lipid membranes, the adhesion strength depended on the surface concentration of Mfn1 through a cooperative binding mechanism. We discuss a possible scenario for the outer mitochondrial membrane fusion based on the modulated action of Mfn1.
    Keywords:  GTPase; giant vesicles; membrane fusion; mitochondria; mitofusin 1
    DOI:  https://doi.org/10.3390/biom10071085
  6. Nat Metab. 2020 Jul;2(7): 566-571
    Lactate: the ugly duckling of energy metabolism.
    Joshua D Rabinowitz, Sven Enerbäck.
      Lactate, perhaps the best-known metabolic waste product, was first isolated from sour milk, in which it is produced by lactobacilli. Whereas microbes also generate other fermentation products, such as ethanol or acetone, lactate dominates in mammals. Lactate production increases when the demand for ATP and oxygen exceeds supply, as occurs during intense exercise and ischaemia. The build-up of lactate in stressed muscle and ischaemic tissues has established lactate's reputation as a deleterious waste product. In this Perspective, we summarize emerging evidence that, in mammals, lactate also serves as a major circulating carbohydrate fuel. By providing mammalian cells with both a convenient source and sink for three-carbon compounds, circulating lactate enables the uncoupling of carbohydrate-driven mitochondrial energy generation from glycolysis. Lactate and pyruvate together serve as a circulating redox buffer that equilibrates the NADH/NAD ratio across cells and tissues. This reconceptualization of lactate as a fuel-analogous to how Hans Christian Andersen's ugly duckling is actually a beautiful swan-has the potential to reshape the field of energy metabolism.
    DOI:  https://doi.org/10.1038/s42255-020-0243-4
  7. Neurobiol Dis. 2020 Jul 16. pii: S0969-9961(20)30295-3. [Epub ahead of print] 105020
    Disruption of endoplasmic reticulum-mitochondria tethering proteins in post-mortem Alzheimer's disease brain.
    Dawn H W Lau, Sebastien Paillusson, Naomi Hartopp, Huzefa Rupawala, Gábor M Mórotz, Patricia Gomez-Suaga, Jenny Greig, Claire Troakes, Wendy Noble, Christopher C J Miller.
      Signaling between the endoplasmic reticulum (ER) and mitochondria regulates a number of key neuronal functions, many of which are perturbed in Alzheimer's disease. Moreover, damage to ER-mitochondria signaling is seen in cell and transgenic models of Alzheimer's disease. However, as yet there is little evidence that ER-mitochondria signaling is altered in human Alzheimer's disease brains. ER-mitochondria signaling is mediated by interactions between the integral ER protein VAPB and the outer mitochondrial membrane protein PTPIP51 which act to recruit and "tether" regions of ER to the mitochondrial surface. The VAPB-PTPIP51 tethers are now known to regulate a number of ER-mitochondria signaling functions including delivery of Ca2+from ER stores to mitochondria, mitochondrial ATP production, autophagy and synaptic activity. Here we investigate the VAPB-PTPIP51 tethers in post-mortem control and Alzheimer's disease brains. Quantification of ER-mitochondria signaling proteins by immunoblotting revealed loss of VAPB and PTPIP51 in cortex but not cerebellum at end-stage Alzheimer's disease. Proximity ligation assays were used to quantify the VAPB-PTPIP51 interaction in temporal cortex pyramidal neurons and cerebellar Purkinje cell neurons in control, Braak stage III-IV (early/mid-dementia) and Braak stage VI (severe dementia) cases. Pyramidal neurons degenerate in Alzheimer's disease whereas Purkinje cells are less affected. These studies revealed that the VAPB-PTPIP51 tethers are disrupted in Braak stage III-IV pyramidal but not Purkinje cell neurons. Thus, we identify a new pathogenic event in post-mortem Alzheimer's disease brains. The implications of our findings for Alzheimer's disease mechanisms are discussed.
    Keywords:  Alzheimer's disease; Endoplasmic reticulum; Mitochondria; PTPIP51; VAPB
    DOI:  https://doi.org/10.1016/j.nbd.2020.105020
  8. Proc Natl Acad Sci U S A. 2020 Jul 20. pii: 202010682. [Epub ahead of print]
    Last step in the path of LDL cholesterol from lysosome to plasma membrane to ER is governed by phosphatidylserine.
    Michael N Trinh, Michael S Brown, Joseph L Goldstein, Jaeil Han, Gonçalo Vale, Jeffrey G McDonald, Joachim Seemann, Joshua T Mendell, Feiran Lu.
      Animal cells acquire cholesterol from receptor-mediated uptake of low-density lipoprotein (LDL), which releases cholesterol in lysosomes. The cholesterol moves to the endoplasmic reticulum (ER), where it inhibits production of LDL receptors, completing a feedback loop. Here we performed a CRISPR-Cas9 screen in human SV589 cells for genes required for LDL-derived cholesterol to reach the ER. We identified the gene encoding PTDSS1, an enzyme that synthesizes phosphatidylserine (PS), a phospholipid constituent of the inner layer of the plasma membrane (PM). In PTDSS1-deficient cells where PS is low, LDL cholesterol leaves lysosomes but fails to reach the ER, instead accumulating in the PM. The addition of PS restores cholesterol transport to the ER. We conclude that LDL cholesterol normally moves from lysosomes to the PM. When the PM cholesterol exceeds a threshold, excess cholesterol moves to the ER in a process requiring PS. In the ER, excess cholesterol acts to reduce cholesterol uptake, preventing toxic cholesterol accumulation. These studies reveal that one lipid-PS-controls the movement of another lipid-cholesterol-between cell membranes. We relate these findings to recent evidence indicating that PM-to-ER cholesterol transport is mediated by GRAMD1/Aster proteins that bind PS and cholesterol.
    Keywords:  CRISPR screen; PTDSS1; cholesterol; phosphatidylserine; plasma membrane
    DOI:  https://doi.org/10.1073/pnas.2010682117
  9. J Biol Chem. 2020 Jul 24. 295(30): 10506
    The roles of cytosolic and intramitochondrial Ca2+ and the mitochondrial Ca2+-uniporter (MCU) in the stimulation of mammalian oxidative phosphorylation.
    Guy A Rutter, James G McCormack, Andrew P Halestrap, Richard M Denton.
      
    DOI:  https://doi.org/10.1074/jbc.L120.013975
  10. Biomolecules. 2020 Jul 17. pii: E1068. [Epub ahead of print]10(7):
    The Multifaceted Pyruvate Metabolism: Role of the Mitochondrial Pyruvate Carrier.
    Joséphine Zangari, Francesco Petrelli, Benoît Maillot, Jean-Claude Martinou.
      Pyruvate, the end product of glycolysis, plays a major role in cell metabolism. Produced in the cytosol, it is oxidized in the mitochondria where it fuels the citric acid cycle and boosts oxidative phosphorylation. Its sole entry point into mitochondria is through the recently identified mitochondrial pyruvate carrier (MPC). In this review, we report the latest findings on the physiology of the MPC and we discuss how a dysfunctional MPC can lead to diverse pathologies, including neurodegenerative diseases, metabolic disorders, and cancer.
    Keywords:  cancer; metabolic disorders; metabolism; mitochondria; mitochondrial pyruvate carrier; neurodegeneration
    DOI:  https://doi.org/10.3390/biom10071068
  11. Dev Cell. 2020 Jul 20. pii: S1534-5807(20)30537-2. [Epub ahead of print]54(2): 239-255
    Hematopoietic Stem Cell Metabolism during Development and Aging.
    Ayako Nakamura-Ishizu, Keisuke Ito, Toshio Suda.
      Cellular metabolism in hematopoietic stem cells (HSCs) is an area of intense research interest, but the metabolic requirements of HSCs and their adaptations to their niches during development have remained largely unaddressed. Distinctive from other tissue stem cells, HSCs transition through multiple hematopoietic sites during development. This transition requires drastic metabolic shifts, insinuating the capacity of HSCs to meet the physiological demand of hematopoiesis. In this review, we highlight how mitochondrial metabolism determines HSC fate, and especially focus on the links between mitochondria, endoplasmic reticulum (ER), and lysosomes in HSC metabolism.
    DOI:  https://doi.org/10.1016/j.devcel.2020.06.029
  12. Cell Death Dis. 2020 Jul 24. 11(7): 578
    Altered mitochondrial dynamics and function in APOE4-expressing astrocytes.
    Eran Schmukler, Shira Solomon, Shira Simonovitch, Yona Goldshmit, Eya Wolfson, Daniel Morris Michaelson, Ronit Pinkas-Kramarski.
      APOE4 is a major risk factor for sporadic Alzheimer's disease; however, it is unclear how it exerts its pathological effects. Others and we have previously shown that autophagy is impaired in APOE4 compared to APOE3 astrocytes, and demonstrated differences in the expression of mitochondrial dynamics proteins in brains of APOE3 and APOE4 transgenic mice. Here, we investigated the effect of APOE4 expression on several aspects of mitochondrial function and network dynamics, including fusion, fission, and mitophagy, specifically in astrocytes. We found that APOE3 and APOE4 astrocytes differ in their mitochondrial dynamics, suggesting that the mitochondria of APOE4 astrocytes exhibit reduced fission and mitophagy. APOE4 astrocytes also show impaired mitochondrial function. Importantly, the autophagy inducer rapamycin enhanced mitophagy and improved mitochondrial functioning in APOE4 astrocytes. Collectively, the results demonstrate that APOE4 expression is associated with altered mitochondrial dynamics, which might lead to impaired mitochondrial function in astrocytes. This, in turn, may contribute to the pathological effects of APOE4 in Alzheimer's disease.
    DOI:  https://doi.org/10.1038/s41419-020-02776-4
  13. Nat Chem Biol. 2020 Jul 20.
    Pharmacologic IRE1/XBP1s activation confers targeted ER proteostasis reprogramming.
    Julia M D Grandjean, Aparajita Madhavan, Lauren Cech, Bryan O Seguinot, Ryan J Paxman, Emery Smith, Louis Scampavia, Evan T Powers, Christina B Cooley, Lars Plate, Timothy P Spicer, Jeffery W Kelly, R Luke Wiseman.
      Activation of the IRE1/XBP1s signaling arm of the unfolded protein response (UPR) is a promising strategy to correct defects in endoplasmic reticulum (ER) proteostasis implicated in diverse diseases. However, no pharmacologic activators of this pathway identified to date are suitable for ER proteostasis remodeling through selective activation of IRE1/XBP1s signaling. Here, we use high-throughput screening to identify non-toxic compounds that induce ER proteostasis remodeling through IRE1/XBP1s activation. We employ transcriptional profiling to stringently confirm that our prioritized compounds selectively activate IRE1/XBP1s signaling without activating other cellular stress-responsive signaling pathways. Furthermore, we demonstrate that our compounds improve ER proteostasis of destabilized variants of amyloid precursor protein (APP) through an IRE1-dependent mechanism and reduce APP-associated mitochondrial toxicity in cellular models. These results establish highly selective IRE1/XBP1s activating compounds that can be widely employed to define the functional importance of IRE1/XBP1s activity for ER proteostasis regulation in the context of health and disease.
    DOI:  https://doi.org/10.1038/s41589-020-0584-z
  14. Cancer Discov. 2020 Jul 24.
    Mitochondrial Oxidation of Ubiquinol Is Required for Tumorigenesis.
      The ability of mitochondrial complex III to oxidize ubiquinol was essential to tumor growth in vivo.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2020-107
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