scholarly journals Vacuole phase-partitioning boosts mitochondria activity and cell lifespan through an inter-organelle lipid pipeline

2021 ◽  
Author(s):  
Arnold Y Seo ◽  
Florian Sarkleti ◽  
Itay Budin ◽  
Chi-Lun Chang ◽  
Christopher Ryan King ◽  
...  
Keyword(s):  
Respiratory Activity ◽  
Mitochondrial Activity ◽  
Lipid Domains ◽  
Glucose Starvation ◽  
Lipid Transfer ◽  
Lipid Trafficking ◽  
Phase Partitioning ◽  
Trafficking Pathway ◽  
Functional Linkage ◽  
Activity Energy

Functional linkage between mitochondria and lysosomes is crucial for survival under starvation and lifespan extension. Despite such co-dependency, the supportive pathways connecting mitochondria and lysosomes remain unclear. Here, we identify an inter-organelle lipid trafficking pathway linking yeast vacuole and mitochondria that results in increased mitochondria growth and respiratory activity under glucose starvation. The pathway depends on vacuolar phase-separated, lipid domains, which provide zones for: activation of the vacuolar proton pump; lipid droplet (LD) docking and internalization; and, lipid transfer from vacuole-to-ER-to-mitochondria. Partitioned vacuolar domains form through a specialized type of macro-autophagy, triggered only under acute glucose starvation, that delivers sterol-rich, endosomal-derived lipids to the vacuole. To balance this lipid influx, the vacuole reroutes lipids back to the ER to support both LD biogenesis and mitochondria growth and activity. Energy produced by enhanced mitochondrial activity then feeds back to support the inter-organelle lipid trafficking pathways to ensure survival under nutrient stress.

Spatial and developmental changes in the respiratory activity of mitochondria in early Drosophila embryos

Development ◽  
1992 ◽  
Vol 115 (4) ◽  
pp. 1175-1182 ◽  
Author(s):  
T. Akiyama ◽  
M. Okada
Keyword(s):  
Respiratory Activity ◽  
Cell Formation ◽  
Rhodamine 123 ◽  
Mitochondrial Activity ◽  
Early Cleavage ◽  
Pole Cell ◽  
Posterior Group ◽  
Cleavage Stages ◽  
Pole Cells ◽  
Drosophila Embryos

Mitochondria of early Drosophila embryos were observed with a transmission electron microscope and a fluorescent microscope after vital staining with rhodamine 123, which accumulates only in active mitochondria. Rhodamine 123 accumulated particularly in the posterior pole region in early cleavage embryos, whereas the spatial distribution of mitochondria in an embryo was uniform throughout cleavage stages. In late cleavage stages, the dye showed very weak and uniform accumulation in all regions of periplasm. Polar plasm, sequestered in pole cells, restored the ability to accumulate the dye. Therefore, it is concluded that the respiratory activity of mitochondria is higher in the polar plasm than in the other regions of periplasm in early embryos, and this changes during development. The temporal changes in rhodamine 123-staining of polar plasm were not affected by u.v. irradiation at the posterior of early cleavage embryos at a sufficient dosage to prevent pole cell formation. This suggests that the inhibition of pole cell formation by u.v. irradiation is not due to the inactivation of the respiratory activities of mitochondria. In addition, we found that the anterior of Bicaudal-D mutant embryos at cleavage stage was stained with rhodamine 123 with the same intensity as the posterior of wild-type embryos. No pole cells form in the anterior of Bic-D embryos, where no restoration of mitochondrial activity occurs in the blastoderm stage. The posterior group mutations that we tested (staufen, oskar, tudor, nanos) and the terminal mutation (torso) did not alter staining pattern of the posterior with rhodamine 123.

Chloroplast lipid synthesis and lipid trafficking through ER–plastid membrane contact sites

2012 ◽  
Vol 40 (2) ◽  
pp. 457-463 ◽  
Author(s):  
Zhen Wang ◽  
Christoph Benning
Keyword(s):  
Fatty Acids ◽  
Current Knowledge ◽  
Lipid Transfer ◽  
Photosynthetic Membrane ◽  
Lipid Trafficking ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Membrane Contact ◽  
Envelope Membranes ◽  
Thylakoid Lipids

Plant chloroplasts contain an intricate photosynthetic membrane system, the thylakoids, and are surrounded by two envelope membranes at which thylakoid lipids are assembled. The glycoglycerolipids mono- and digalactosyldiacylglycerol, and sulfoquinovosyldiacylglycerol as well as phosphatidylglycerol, are present in thylakoid membranes, giving them a unique composition. Fatty acids are synthesized in the chloroplast and are either directly assembled into thylakoid lipids at the envelope membranes or exported to the ER (endoplasmic reticulum) for extraplastidic lipid assembly. A fraction of lipid precursors is reimported into the chloroplast for the synthesis of thylakoid lipids. Thus polar lipid assembly in plants requires tight co-ordination between the chloroplast and the ER and necessitates inter-organelle lipid trafficking. In the present paper, we discuss the current knowledge of the export of fatty acids from the chloroplast and the import of chloroplast lipid precursors assembled at the ER. Direct membrane contact sites between the ER and the chloroplast outer envelopes are discussed as possible conduits for lipid transfer.

scholarly journals LENG8 regulation of mRNA processing is responsible for the control of mitochondrial activity

2021 ◽  
Author(s):  
Yongxu Zhao ◽  
Xiaoting Wang ◽  
Yuenan Liu ◽  
Niannian Li ◽  
Shengming Wang ◽  
...  
Keyword(s):  
Nuclear Export ◽  
Mammalian Cells ◽  
Respiratory Activity ◽  
Mrna Processing ◽  
Mitochondrial Activity ◽  
Processing Factor ◽  
Conditional Deletion ◽  
Evolutionarily Conserved ◽  
Murine Fibroblasts ◽  
Mitochondrial Respiratory Activity

Abstract The processing of mRNA is essential for the maintenance of cellular and tissue homeostasis. However, the precise regulation of this process in mammalian cells, remains largely unknown. Here we have found that LENG8 represents the mammalian orthologue of the yeast mRNA processing factor Thp3 and Sac3. We go on to demonstrate that LENG8 binds to mRNAs, associates with components of mRNA processing machinery (the TREX complex) and contributes to mRNA nuclear export to the cytoplasm. Loss of LENG8 , leads to aberrant accumulation of poly (A) + RNA in the nucleus, in both Hela cells and murine fibroblasts. Furthermore, the precipitation of LENG8, is associated with an enrichment of both mRNAs and lncRNAs, and approximately half of these are also bound by the TREX component, THOC1. However, LENG8 preferentially binds mRNAs encoding for mitochondrial proteins and depletion of this processing factor, causes a dramatic breakdown in mitochondrial ultrastructure and a reduction in mitochondrial respiratory activity. Conditional deletion of Leng8 in mouse adipose tissues lead to a decreased body weight, and increased adipose thermogenesis. Our work has found an evolutionarily conserved mRNA processing factor that can control mitochondrial activity.

scholarly journals Is Spontaneous Translocation of Polar Lipids between Cellular Organelles Negligible?

2015 ◽  
Vol 8s1 ◽  
pp. LPI.S31616 ◽  
Author(s):  
Pentti Somerharju
Keyword(s):  
Polar Lipids ◽  
Lipid Transfer ◽  
Organelle Biogenesis ◽  
Single Chain ◽  
Experimental Conditions ◽  
Lipid Trafficking ◽  
Acyl Chains ◽  
Highly Hydrophobic ◽  
Cellular Organelles

In most reviews addressing intracellular lipid trafficking, spontaneous diffusion of lipid monomers between the cellular organelles is considered biologically irrelevant because it is thought to be far too slow to significantly contribute to organelle biogenesis. This view is based on intervesicle transfer experiments carried out in vitro with few lipids as well as on the view that lipids are highly hydrophobic and thus cannot undergo spontaneous intermembrane diffusion at a significant rate. However, besides that single-chain lipids can translocate between vesicles in seconds, it has been demonstrated that the rate of spontaneous transfer of two-chain polar lipids can vary even 1000-fold, depending on the number of carbons and double bonds in the acyl chains. In addition, the rate of spontaneous lipid transfer can strongly depend on the experimental conditions such as vesicle composition and concentration. This review examines the studies suggesting that spontaneous lipid transfer is probably more relevant to intracellular trafficking of amphipathic lipids than commonly thought.

scholarly journals Lipid Metabolism at Membrane Contacts: Dynamics and Functions Beyond Lipid Homeostasis

2020 ◽  
Vol 8 ◽  
Author(s):  
Jiesi Xu ◽  
Xun Huang
Keyword(s):  
Lipid Metabolism ◽  
Intracellular Signaling ◽  
Dynamic Control ◽  
Lipid Synthesis ◽  
Lipid Homeostasis ◽  
Lipid Transfer ◽  
Organelle Biogenesis ◽  
Lipid Trafficking ◽  
Membrane Contact Sites ◽  
Membrane Contacts

Membrane contact sites (MCSs), regions where the membranes of two organelles are closely apposed, play critical roles in inter-organelle communication, such as lipid trafficking, intracellular signaling, and organelle biogenesis and division. First identified as “fraction X” in the early 90s, MCSs are now widely recognized to facilitate local lipid synthesis and inter-organelle lipid transfer, which are important for maintaining cellular lipid homeostasis. In this review, we discuss lipid metabolism and related cellular and physiological functions in MCSs. We start with the characteristics of lipid synthesis and breakdown at MCSs. Then we focus on proteins involved in lipid synthesis and turnover at these sites. Lastly, we summarize the cellular function of lipid metabolism at MCSs beyond mere lipid homeostasis, including the physiological meaning and relevance of MCSs regarding systemic lipid metabolism. This article is part of an article collection entitled: Coupling and Uncoupling: Dynamic Control of Membrane Contacts.

scholarly journals High-Throughput Screening Identified Compounds Sensitizing Tumor Cells to Glucose Starvation in Culture and VEGF Inhibitors In Vivo

Cancers ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 156 ◽  
Author(s):  
Ran Marciano ◽  
Manu Prasad ◽  
Tal Ievy ◽  
Sapir Tzadok ◽  
Gabriel Leprivier ◽  
...  
Keyword(s):  
Tumor Cells ◽  
High Throughput ◽  
High Throughput Screening ◽  
Therapeutic Strategy ◽  
Xenograft Model ◽  
Tumor Xenograft ◽  
Mitochondrial Activity ◽  
Glucose Starvation ◽  
Normal Medium

Tumor cells utilize glucose to fuel their anabolic needs, including rapid proliferation. However, due to defective vasculature and increased glucose uptake, tumor cells must overcome glucose deprivation. Accordingly, tumor cells depend on cellular pathways promoting survival under such conditions. Targeting these survival mechanisms can thus serve as a new therapeutic strategy in oncology. As such, we sought to identify small-molecule inhibitors which sensitize tumor cells to glucose starvation by high-throughput drug screening in vitro. Specifically, we searched for inhibitors that selectively killed tumor cells growing in glucose-free but not in normal medium. This phenotypic drug screen of 7000 agents with MCF7 cells led to the identification of 67 potential candidates, 31 of which were validated individually. Among the identified compounds, we found a high number of compounds known to target mitochondria. The efficacies of two of the identified compounds, QNZ (EVP4593) and papaverine, were validated in four different tumor cell lines. We found that these agents inhibited the mTOR(Mechamistic\Mammilian Target of Rapamycin) pathway in tumor cells growing under glucose starvation, but not under normal conditions. The results were validated and confirmed in vivo, with QNZ and papaverine exhibiting superior antitumor activity in a tumor xenograft model when combined with the VEGF inhibitor bevacizumab (avastin). Administering these drug combinations (i.e., avastin and papaverine, and avastin and QNZ) led to significant reductions in proliferation and mTOR activity of the aggressive DLD1 colon cell line in mice. Given our findings, we propose that compounds targeting metabolically challenged tumors, such as inhibitors of mitochondrial activity, be considered as a therapeutic strategy in cancer.

scholarly journals Lipid homeostasis in mitochondria

2020 ◽  
Vol 401 (6-7) ◽  
pp. 821-833
Author(s):  
Yasushi Tamura ◽  
Shin Kawano ◽  
Toshiya Endo
Keyword(s):  
Lipid Homeostasis ◽  
Structural Basis ◽  
Lipid Transfer ◽  
Lipid Transfer Proteins ◽  
Lipid Trafficking ◽  
Contact Sites ◽  
Mitochondrial Lipid ◽  
Proper Functions ◽  
Mitochondrial Lipids

AbstractMitochondria are surrounded by the two membranes, the outer and inner membranes, whose lipid compositions are optimized for proper functions and structural organizations of mitochondria. Although a part of mitochondrial lipids including their characteristic lipids, phosphatidylethanolamine and cardiolipin, are synthesized within mitochondria, their precursor lipids and other lipids are transported from other organelles, mainly the ER. Mitochondrially synthesized lipids are re-distributed within mitochondria and to other organelles, as well. Recent studies pointed to the important roles of inter-organelle contact sites in lipid trafficking between different organelle membranes. Identification of Ups/PRELI proteins as lipid transfer proteins shuttling between the mitochondrial outer and inner membranes established a part of the molecular and structural basis of the still elusive intra-mitochondrial lipid trafficking.

Lipid trafficking between the endoplasmic reticulum and the chloroplast

2006 ◽  
Vol 34 (3) ◽  
pp. 395-398 ◽  
Author(s):  
K. Awai ◽  
C. Xu ◽  
B. Lu ◽  
C. Benning
Keyword(s):  
Endoplasmic Reticulum ◽  
Thylakoid Membrane ◽  
Atmospheric Oxygen ◽  
Photosynthetic Apparatus ◽  
Membrane System ◽  
Chloroplast Envelope ◽  
Lipid Transfer ◽  
Lipid Trafficking ◽  
Model Plant Arabidopsis Thaliana ◽  
Extensive Exchange

The photosynthetic (thylakoid) membrane of plants is one of the most extensive biological cell membrane systems found in Nature. It harbours the photosynthetic apparatus, which is essential to life on Earth as carbon dioxide is fixed and atmospheric oxygen released by photosynthesis. Lipid biosynthetic enzymes of different subcellular compartments participate in the biogenesis of the thylakoid membrane system. This process requires the extensive exchange of lipid precursors between the chloroplast and the ER (endoplasmic reticulum). The underlying lipid trafficking phenomena are not yet understood at the mechanistic level, but genetic mutants of the model plant Arabidopsis thaliana with disruptions in lipid trafficking between the ER and the chloroplast have recently become available. Their study has led to the identification of components of the lipid transfer machinery at the inner chloroplast envelope.

scholarly journals LENG8 regulation of mRNA processing, is responsible for the control of mitochondrial activity

2021 ◽  
Author(s):  
Yongxu Zhao ◽  
Xiaoting Wang ◽  
Niannian Li ◽  
Yuenan Liu ◽  
Zhigang Sun ◽  
...  
Keyword(s):  
Nuclear Export ◽  
Mammalian Cells ◽  
Respiratory Activity ◽  
Mrna Processing ◽  
Mitochondrial Activity ◽  
Processing Factor ◽  
Conditional Deletion ◽  
Evolutionarily Conserved ◽  
Murine Fibroblasts ◽  
Mitochondrial Respiratory Activity

The processing of mRNA is essential for the maintenance of cellular and tissue homeostasis. However, the precise regulation of this process in mammalian cells, remains largely unknown. Here we have found that LENG8 represents the mammalian orthologue of the yeast mRNA processing factor Thp3 and Sac3. We go on to demonstrate that LENG8 binds to mRNAs, associates with components of mRNA processing machinery (the TREX complex) and contributes to mRNA nuclear export to the cytoplasm. Loss of LENG8, leads to aberrant accumulation of poly (A)+ RNA in the nucleus, in both Hela cells and murine fibroblasts. Furthermore, the precipitation of LENG8, is associated with an enrichment of both mRNAs and lncRNAs, and approximately half of these are also bound by the TREX component, THOC1. However, LENG8 preferentially binds mRNAs encoding for mitochondrial proteins and depletion of this processing factor, causes a dramatic breakdown in mitochondrial ultrastructure and a reduction in mitochondrial respiratory activity. Conditional deletion of Leng8 in mouse adipose tissues lead to a decreased body weight, and increased adipose thermogenesis. Our work has found an evolutionarily conserved mRNA processing factor that can control mitochondrial activity.

Sign in / Sign up

Export Citation Format

Share Document