scholarly journals Sterol transporters at membrane contact sites regulate TORC1 and TORC2 signaling

2017 ◽  
Vol 216 (9) ◽  
pp. 2679-2689 ◽  
Author(s):  
Andrew Murley ◽  
Justin Yamada ◽  
Bradley J. Niles ◽  
Alexandre Toulmay ◽  
William A. Prinz ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Stress Responses ◽  
Membrane Dynamics ◽  
Membrane Domains ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Sterol Transport ◽  
Cellular Stress Responses ◽  
Membrane Contact ◽  
Upstream Regulators

Membrane contact sites (MCSs) function to facilitate the formation of membrane domains composed of specialized lipids, proteins, and nucleic acids. In cells, membrane domains regulate membrane dynamics and biochemical and signaling pathways. We and others identified a highly conserved family of sterol transport proteins (Ltc/Lam) localized at diverse MCSs. In this study, we describe data indicating that the yeast family members Ltc1 and Ltc3/4 function at the vacuole and plasma membrane, respectively, to create membrane domains that partition upstream regulators of the TORC1 and TORC2 signaling pathways to coordinate cellular stress responses with sterol homeostasis.

scholarly journals Role of membrane contact sites in PM ‐ ER sterol transport (606.7)

2014 ◽  
Vol 28 (S1) ◽  
Author(s):  
Yves Sere ◽  
Jesper Johansen ◽  
Christopher Beh ◽  
Anant Menon
Keyword(s):  
Membrane Contact Sites ◽  
Contact Sites ◽  
Sterol Transport ◽  
Membrane Contact

scholarly journals Quantitative imaging of membrane contact sites for sterol transfer between endo-lysosomes and mitochondria in living cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Alice Dupont Juhl ◽  
Christian W. Heegaard ◽  
Stephan Werner ◽  
Gerd Schneider ◽  
Kathiresan Krishnan ◽  
...  
Keyword(s):  
Close Contact ◽  
Quantitative Imaging ◽  
Human Fibroblasts ◽  
Time Lapse ◽  
Living Cells ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Sterol Transport ◽  
Membrane Contact ◽  
Niemann Pick

AbstractMitochondria receive cholesterol from late endosomes and lysosomes (LE/LYSs) or from the plasma membrane for production of oxysterols and steroid hormones. This process depends on the endo-lysosomal sterol transfer protein Niemann Pick C2 (NPC2). Using the intrinsically fluorescent cholesterol analog, cholestatrienol, we directly observe sterol transport to mitochondria in fibroblasts upon treating NPC2 deficient human fibroblasts with NPC2 protein. Soft X-ray tomography reveals the ultrastructure of mitochondria and discloses close contact to endosome-like organelles. Using fluorescence microscopy, we localize endo-lysosomes containing NPC2 relative to mitochondria based on the Euclidian distance transform and use statistical inference to show that about 30% of such LE/LYSs are in contact to mitochondria in human fibroblasts. Using Markov Chain Monte Carlo image simulations, we show that interaction between both organelle types, a defining feature of membrane contact sites (MCSs) can give rise to the observed spatial organelle distribution. We devise a protocol to determine the surface fraction of endo-lysosomes in contact with mitochondria and show that this fraction does not depend on functional NPC1 or NPC2 proteins. Finally, we localize MCSs between LE/LYSs containing NPC2 and mitochondria in time-lapse image sequences and show that they either form transiently or remain stable for tens of seconds. Lasting MCSs between endo-lysosomes containing NPC2 and mitochondria move by slow anomalous sub-diffusion, providing location and time for sterol transport between both organelles. Our quantitative imaging strategy will be of high value for characterizing the dynamics and function of MCSs between various organelles in living cells.

scholarly journals Fission and fusion machineries converge at ER contact sites to regulate mitochondrial morphology

2020 ◽  
Vol 219 (4) ◽  
Author(s):  
Robert G. Abrisch ◽  
Samantha C. Gumbin ◽  
Brett Taylor Wisniewski ◽  
Laura L. Lackner ◽  
Gia K. Voeltz
Keyword(s):  
Steady State ◽  
Mitochondrial Fission ◽  
Membrane Dynamics ◽  
Mitochondrial Morphology ◽  
Mitochondrial Network ◽  
Fusion Reactions ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Metabolic States ◽  
Membrane Contact

The steady-state morphology of the mitochondrial network is maintained by a balance of constitutive fission and fusion reactions. Disruption of this steady-state morphology results in either a fragmented or elongated network, both of which are associated with altered metabolic states and disease. How the processes of fission and fusion are balanced by the cell is unclear. Here we show that mitochondrial fission and fusion are spatially coordinated at ER membrane contact sites (MCSs). Multiple measures indicate that the mitochondrial fusion machinery, Mitofusins, accumulate at ER MCSs where fusion occurs. Furthermore, fission and fusion machineries colocalize to form hotspots for membrane dynamics at ER MCSs that can persist through sequential events. Because these hotspots can undergo fission and fusion, they have the potential to quickly respond to metabolic cues. Indeed, we discover that ER MCSs define the interface between polarized and depolarized segments of mitochondria and can rescue the membrane potential of damaged mitochondria by ER-associated fusion.

scholarly journals A new family of StART domain proteins at membrane contact sites has a role in ER-PM sterol transport

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Alberto T Gatta ◽  
Louise H Wong ◽  
Yves Y Sere ◽  
Diana M Calderón-Noreña ◽  
Shamshad Cockcroft ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Plasma Membrane ◽  
Lipid Transfer ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
New Family ◽  
Sterol Transport ◽  
In Trans ◽  
Membrane Contact ◽  
Start Domain

Sterol traffic between the endoplasmic reticulum (ER) and plasma membrane (PM) is a fundamental cellular process that occurs by a poorly understood non-vesicular mechanism. We identified a novel, evolutionarily diverse family of ER membrane proteins with StART-like lipid transfer domains and studied them in yeast. StART-like domains from Ysp2p and its paralog Lam4p specifically bind sterols, and Ysp2p, Lam4p and their homologs Ysp1p and Sip3p target punctate ER-PM contact sites distinct from those occupied by known ER-PM tethers. The activity of Ysp2p, reflected in amphotericin-sensitivity assays, requires its second StART-like domain to be positioned so that it can reach across ER-PM contacts. Absence of Ysp2p, Ysp1p or Sip3p reduces the rate at which exogenously supplied sterols traffic from the PM to the ER. Our data suggest that these StART-like proteins act in trans to mediate a step in sterol exchange between the PM and ER.

scholarly journals Author response: A new family of StART domain proteins at membrane contact sites has a role in ER-PM sterol transport

2015 ◽  
Author(s):  
Alberto T Gatta ◽  
Louise H Wong ◽  
Yves Y Sere ◽  
Diana M Calderón-Noreña ◽  
Shamshad Cockcroft ◽  
...  
Keyword(s):  
Author Response ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
New Family ◽  
Sterol Transport ◽  
Membrane Contact ◽  
Start Domain
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