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 VPS13D interacts with VCP/p97 and negatively regulates ER- mitochondrial interactions

2021 ◽  
pp. mbc.E21-03-0097
Author(s):  
Yuanjiao Du ◽  
Jingru Wang ◽  
Juan Xiong ◽  
Na Fang ◽  
Wei-Ke Ji
Keyword(s):  
Negative Regulation ◽  
Mitochondrial Morphology ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Cellular Events ◽  
Membrane Contact ◽  
The Stability ◽  
Vacuolar Protein ◽  
Mitochondrial Dna Synthesis

Membrane contact sites (MCSs) between the endoplasmic reticulum (ER) and mitochondria are emerging as critical hubs for diverse cellular events, and alterations in the extent of these contacts are linked to neurodegenerative diseases. However, the mechanisms that control ER-mitochondrial interactions are so far elusive. Here, we demonstrate a key role of vacuolar protein sorting-associated protein 13D (VPS13D) in the negative regulation of ER-mitochondrial MCSs. VPS13D suppression results in extensive ER-mitochondrial tethering, a phenotype that can be substantially rescued by suppression of the tethering proteins VAPB and PTPIP51. VPS13D interacts with valosin-containing protein (VCP/p97) to control the level of ER-resident VAPB at contacts. VPS13D is required for the stability of p97. Functionally, VPS13D suppression leads to severe defects in the mitochondrial morphology, mitochondrial cellular distribution and mitochondrial DNA synthesis. Together our results suggest that VPS13D negatively regulates the ER-mitochondrial MCSs partially through its interactions with VCP/p97. [Media: see text]

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 Caenorhabditis elegans Junctophilin has tissue-specific functions and regulates neurotransmission with extended-synaptotagmin

Genetics ◽  
2021 ◽  
Author(s):  
Christopher A Piggott ◽  
Zilu Wu ◽  
Stephen Nurrish ◽  
Suhong Xu ◽  
Joshua M Kaplan ◽  
...  
Keyword(s):  
Calcium Channels ◽  
Calcium Channel ◽  
Tissue Specific ◽  
Voltage Gated ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Pharyngeal Muscles ◽  
Membrane Contact ◽  
Null Mutants

Abstract The junctophilin family of proteins tether together plasma membrane (PM) and endoplasmic reticulum (ER) membranes, and couple PM- and ER-localized calcium channels. Understanding in vivo functions of junctophilins is of great interest for dissecting the physiological roles of ER-PM contact sites. Here, we show that the sole C. elegans junctophilin JPH-1 localizes to discrete membrane contact sites in neurons and muscles and has important tissue-specific functions. jph-1 null mutants display slow growth and development due to weaker contraction of pharyngeal muscles, leading to reduced feeding. In the body wall muscle, JPH-1 co-localizes with the PM-localized EGL-19 voltage-gated calcium channel and ER-localized UNC-68/RyR calcium channel, and is required for animal movement. In neurons, JPH-1 co-localizes with the membrane contact site protein Extended-SYnaptoTagmin 2 (ESYT-2) in soma, and is present near presynaptic release sites. Interestingly, jph-1 and esyt-2 null mutants display mutual suppression in their response to aldicarb, suggesting that JPH-1 and ESYT-2 have antagonistic roles in neuromuscular synaptic transmission. Additionally, we find an unexpected cell non-autonomous effect of jph-1 in axon regrowth after injury. Genetic double mutant analysis suggests that jph-1 functions in overlapping pathways with two PM-localized voltage-gated calcium channels, egl-19 and unc-2, and unc-68/RyR for animal health and development. Finally, we show that jph-1 regulates the colocalization of EGL-19 and UNC-68 and that unc-68/RyR is required for JPH-1 localization to ER-PM puncta. Our data demonstrate important roles for junctophilin in cellular physiology, and also provide insights into how junctophilin functions together with other calcium channels in vivo.

scholarly journals Remodelling of Nucleus-Vacuole Junctions During Metabolic and Proteostatic Stress

Contact ◽  
2021 ◽  
Vol 4 ◽  
pp. 251525642110166
Author(s):  
Verena Kohler ◽  
Sabrina Büttner
Keyword(s):  
Nuclear Envelope ◽  
Internal Stress ◽  
Molecular Architecture ◽  
Adaptation To Stress ◽  
Semipermeable Membranes ◽  
Cellular Adaptation ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Intracellular Compartments ◽  
Membrane Contact

Cellular adaptation to stress and metabolic cues requires a coordinated response of different intracellular compartments, separated by semipermeable membranes. One way to facilitate interorganellar communication is via membrane contact sites, physical bridges between opposing organellar membranes formed by an array of tethering machineries. These contact sites are highly dynamic and establish an interconnected organellar network able to quickly respond to external and internal stress by changing size, abundance and molecular architecture. Here, we discuss recent work on nucleus-vacuole junctions, connecting yeast vacuoles with the nucleus. Appearing as small, single foci in mitotic cells, these contacts expand into one enlarged patch upon nutrient exhaustion and entry into quiescence or can be shaped into multiple large foci essential to sustain viability upon proteostatic stress at the nuclear envelope. We highlight the remarkable plasticity and rapid remodelling of these contact sites upon metabolic or proteostatic stress and their emerging importance for cellular fitness.

scholarly journals Synaptotagmins at the endoplasmic reticulum–plasma membrane contact sites maintain diacylglycerol homeostasis during abiotic stress

2021 ◽  
Author(s):  
Noemi Ruiz-Lopez ◽  
Jessica Pérez-Sancho ◽  
Alicia Esteban del Valle ◽  
Richard P Haslam ◽  
Steffen Vanneste ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Plasma Membrane ◽  
Abiotic Stress ◽  
Fluorescent Protein ◽  
Mechanical Damage ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Membrane Contact ◽  
Green Fluorescent

Abstract Endoplasmic reticulum-plasma membrane contact sites (ER-PM CS) play fundamental roles in all eukaryotic cells. Arabidopsis thaliana mutants lacking the ER-PM protein tether synaptotagmin1 (SYT1) exhibit decreased plasma membrane (PM) integrity under multiple abiotic stresses such as freezing, high salt, osmotic stress and mechanical damage. Here, we show that, together with SYT1, the stress-induced SYT3 is an ER-PM tether that also functions in maintaining PM integrity. The ER-PM CS localization of SYT1 and SYT3 is dependent on PM phosphatidylinositol-4-phosphate and is regulated by abiotic stress. Lipidomic analysis revealed that cold stress increased the accumulation of diacylglycerol at the PM in a syt1/3 double mutant relative to wild type while the levels of most glycerolipid species remain unchanged. Additionally, the SYT1-green fluorescent protein (GFP) fusion preferentially binds diacylglycerol in vivo with little affinity for polar glycerolipids. Our work uncovers a SYT-dependent mechanism of stress adaptation counteracting the detrimental accumulation of diacylglycerol at the PM produced during episodes of abiotic stress.

Regulation and physiology of membrane contact sites

2021 ◽  
Vol 71 ◽  
pp. 148-157
Author(s):  
Rossella Venditti ◽  
Cathal Wilson ◽  
Maria Antonietta De Matteis
Keyword(s):  
Membrane Contact Sites ◽  
Contact Sites ◽  
Membrane Contact
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