scholarly journals Spastin tethers lipid droplets to peroxisomes and directs fatty acid trafficking through ESCRT-III

2019 ◽  
Author(s):  
Chi-Lun Chang ◽  
Aubrey V. Weigel ◽  
Maria S. Ioannou ◽  
H. Amalia Pasolli ◽  
C. Shan Xu ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Fatty Acid ◽  
Hereditary Spastic Paraplegia ◽  
Lipid Droplets ◽  
Spastic Paraplegia ◽  
Dual Roles ◽  
Aaa Atpase ◽  
Contact Sites ◽  
Membrane Morphology ◽  
Membrane Bound

AbstractLipid droplets (LDs) are neutral lipid storage organelles that transfer lipids to various organelles including peroxisomes. Here, we show that the hereditary spastic paraplegia protein M1 Spastin, a membrane-bound AAA ATPase found on LDs, coordinates fatty acid (FA) trafficking from LDs to peroxisomes through two inter-related mechanisms. First, M1 Spastin forms a tethering complex with peroxisomal ABCD1 to promote LD-peroxisome contact formation. Second, M1 Spastin recruits the membrane-shaping ESCRT-III proteins IST1 and CHMP1B to LDs via its MIT domain to facilitate LD-to-peroxisome FA trafficking, possibly through IST1 and CHMP1B modifying LD membrane morphology. Furthermore, M1 Spastin, IST1 and CHMP1B are all required to relieve LDs of lipid peroxidation. M1 Spastin’s dual roles in tethering LDs to peroxisomes and in recruiting ESCRT-components to LD-peroxisome contact sites for FA trafficking may help explain the pathogenesis of diseases associated with defective FA metabolism in LDs and peroxisomes.

scholarly journals Spastin tethers lipid droplets to peroxisomes and directs fatty acid trafficking through ESCRT-III

2019 ◽  
Vol 218 (8) ◽  
pp. 2583-2599 ◽  
Author(s):  
Chi-Lun Chang ◽  
Aubrey V. Weigel ◽  
Maria S. Ioannou ◽  
H. Amalia Pasolli ◽  
C. Shan Xu ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Fatty Acid ◽  
Hereditary Spastic Paraplegia ◽  
Lipid Droplets ◽  
Spastic Paraplegia ◽  
Dual Roles ◽  
Aaa Atpase ◽  
Contact Sites ◽  
Membrane Morphology ◽  
Membrane Bound

Lipid droplets (LDs) are neutral lipid storage organelles that transfer lipids to various organelles including peroxisomes. Here, we show that the hereditary spastic paraplegia protein M1 Spastin, a membrane-bound AAA ATPase found on LDs, coordinates fatty acid (FA) trafficking from LDs to peroxisomes through two interrelated mechanisms. First, M1 Spastin forms a tethering complex with peroxisomal ABCD1 to promote LD–peroxisome contact formation. Second, M1 Spastin recruits the membrane-shaping ESCRT-III proteins IST1 and CHMP1B to LDs via its MIT domain to facilitate LD-to-peroxisome FA trafficking, possibly through IST1- and CHMP1B-dependent modifications in LD membrane morphology. Furthermore, LD-to-peroxisome FA trafficking mediated by M1 Spastin is required to relieve LDs of lipid peroxidation. M1 Spastin’s dual roles in tethering LDs to peroxisomes and in recruiting ESCRT-III components to LD–peroxisome contact sites for FA trafficking may underlie the pathogenesis of diseases associated with defective FA metabolism in LDs and peroxisomes.

scholarly journals Alteration of Fatty-Acid-Metabolizing Enzymes Affects Mitochondrial Form and Function in Hereditary Spastic Paraplegia

2012 ◽  
Vol 91 (6) ◽  
pp. 1051-1064 ◽  
Author(s):  
Christelle Tesson ◽  
Magdalena Nawara ◽  
Mustafa A.M. Salih ◽  
Rodrigue Rossignol ◽  
Maha S. Zaki ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Hereditary Spastic Paraplegia ◽  
Spastic Paraplegia ◽  
Metabolizing Enzymes ◽  
Form And Function ◽  
And Function

scholarly journals Peroxisomal Membrane Contact Sites in Yeasts

2021 ◽  
Vol 9 ◽  
Author(s):  
Amit S. Joshi
Keyword(s):  
Lipid Droplets ◽  
Peroxisome Biogenesis ◽  
Functional Importance ◽  
Peroxisomal Membrane ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Recent Developments ◽  
Membrane Contacts ◽  
Membrane Bound ◽  
Membrane Contact

Peroxisomes are ubiquitous, single membrane-bound organelles that play a crucial role in lipid metabolism and human health. While peroxisome number is maintained by the division of existing peroxisomes, nascent peroxisomes can be generated from the endoplasmic reticulum (ER) membrane in yeasts. During formation and proliferation, peroxisomes maintain membrane contacts with the ER. In addition to the ER, contacts between peroxisomes and other organelles such as lipid droplets, mitochondria, vacuole, and plasma membrane have been reported. These membrane contact sites (MCS) are dynamic and important for cellular function. This review focuses on the recent developments in peroxisome biogenesis and the functional importance of peroxisomal MCS in yeasts.

scholarly journals Microtubule-dependent and independent roles of spastin in lipid droplet dispersion and biogenesis

2020 ◽  
Vol 3 (6) ◽  
pp. e202000715
Author(s):  
Nimesha Tadepalle ◽  
Lennart Robers ◽  
Matteo Veronese ◽  
Peter Zentis ◽  
Felix Babatz ◽  
...  
Keyword(s):  
Hereditary Spastic Paraplegia ◽  
Mammalian Cells ◽  
Lipid Droplets ◽  
Neutral Lipids ◽  
Plastic Behavior ◽  
Glucose Starvation ◽  
Spastic Paraplegia ◽  
Microtubule Severing ◽  
Tag Accumulation

Lipid droplets (LDs) are metabolic organelles that store neutral lipids and dynamically respond to changes in energy availability by accumulating or mobilizing triacylglycerols (TAGs). How the plastic behavior of LDs is regulated is poorly understood. Hereditary spastic paraplegia is a central motor axonopathy predominantly caused by mutations in SPAST, encoding the microtubule-severing protein spastin. The spastin-M1 isoform localizes to nascent LDs in mammalian cells; however, the mechanistic significance of this targeting is not fully explained. Here, we show that tightly controlled levels of spastin-M1 are required to inhibit LD biogenesis and TAG accumulation. Spastin-M1 maintains the morphogenesis of the ER when TAG synthesis is prevented, independent from microtubule binding. Moreover, spastin plays a microtubule-dependent role in mediating the dispersion of LDs from the ER upon glucose starvation. Our results reveal a dual role of spastin to shape ER tubules and to regulate LD movement along microtubules, opening new perspectives for the pathogenesis of hereditary spastic paraplegia.

scholarly journals Recognition of C-terminal amino acids in tubulin by pore loops in Spastin is important for microtubule severing

2007 ◽  
Vol 176 (7) ◽  
pp. 995-1005 ◽  
Author(s):  
Susan Roehl White ◽  
Katia J. Evans ◽  
Jeffrey Lary ◽  
James L. Cole ◽  
Brett Lauring
Keyword(s):  
Amino Acids ◽  
Conformational Changes ◽  
Hereditary Spastic Paraplegia ◽  
Spastic Paraplegia ◽  
Central Cavity ◽  
Aaa Atpase ◽  
Microtubule Severing ◽  
Microtubule Binding Domain ◽  
Terminal Amino ◽  
Form Ring

Spastin, an AAA ATPase mutated in the neurodegenerative disease hereditary spastic paraplegia, severs microtubules. Many other AAA proteins form ring-shaped hexamers and contain pore loops, which project into the ring's central cavity and act as ratchets that pull on target proteins, leading, in some cases, to conformational changes. We show that Spastin assembles into a hexamer and that loops within the central pore recognize C-terminal amino acids of tubulin. Key pore loop amino acids are required for severing, including one altered by a disease-associated mutation. We also show that Spastin contains a second microtubule binding domain that makes a distinct interaction with microtubules and is required for severing. Given that Spastin engages the MT in two places and that both interactions are required for severing, we propose that severing occurs by forces exerted on the C-terminal tail of tubulin, which results in a conformational change in tubulin, which releases it from the polymer.

scholarly journals ER membranes exhibit phase behavior at sites of organelle contact

2020 ◽  
Vol 117 (13) ◽  
pp. 7225-7235 ◽  
Author(s):  
Christopher King ◽  
Prabuddha Sengupta ◽  
Arnold Y. Seo ◽  
Jennifer Lippincott-Schwartz
Keyword(s):  
Phase Behavior ◽  
Lipid Droplets ◽  
Lipid Domains ◽  
Intact Cells ◽  
Contact Sites ◽  
Dependent Behavior ◽  
Membrane Bound ◽  
Intracellular Vesicles ◽  
Micrometer Scale ◽  
Hypotonic Swelling

The endoplasmic reticulum (ER) is the site of synthesis of secretory and membrane proteins and contacts every organelle of the cell, exchanging lipids and metabolites in a highly regulated manner. How the ER spatially segregates its numerous and diverse functions, including positioning nanoscopic contact sites with other organelles, is unclear. We demonstrate that hypotonic swelling of cells converts the ER and other membrane-bound organelles into micrometer-scale large intracellular vesicles (LICVs) that retain luminal protein content and maintain contact sites with each other through localized organelle tethers. Upon cooling, ER-derived LICVs phase-partition into microscopic domains having different lipid-ordering characteristics, which is reversible upon warming. Ordered ER lipid domains mark contact sites with ER and mitochondria, lipid droplets, endosomes, or plasma membrane, whereas disordered ER lipid domains mark contact sites with lysosomes or peroxisomes. Tethering proteins concentrate at ER–organelle contact sites, allowing time-dependent behavior of lipids and proteins to be studied at these sites. These findings demonstrate that LICVs provide a useful model system for studying the phase behavior and interactive properties of organelles in intact cells.

scholarly journals The Troyer syndrome protein spartin mediates selective autophagy of lipid droplets

2021 ◽  
Author(s):  
Jeeyun Chung ◽  
Joongkyu Park ◽  
Zon Weng Lai ◽  
Talley J. Lambert ◽  
Ruth C. Richards ◽  
...  
Keyword(s):  
Energy Storage ◽  
Motor Cortex ◽  
Hereditary Spastic Paraplegia ◽  
Lipid Droplets ◽  
Molecular Mechanisms ◽  
Lipid Homeostasis ◽  
Spastic Paraplegia ◽  
Selective Autophagy ◽  
Important Pathway ◽  
Syndrome Protein

Lipid droplets (LDs) are crucial organelles for energy storage and lipid homeostasis. Autophagy of LDs is an important pathway for their catabolism, but the molecular mechanisms mediating targeting of LDs for degradation by selective autophagy (lipophagy) are unknown. Here we identify spartin as a receptor localizing to LDs and interacting with core autophagy machinery, and we show that spartin is required to deliver LDs to lysosomes for triglyceride (TG) mobilization. Mutations in SPART (encoding spartin) lead to Troyer syndrome, a form of hereditary spastic paraplegia. We find that interfering with spartin function leads to LD and TG accumulation in motor cortex neurons of mice. Our findings thus identify spartin as a lipophagy receptor and suggest that impaired LD turnover may contribute to Troyer syndrome development.

scholarly journals Loss of swiss cheese in Neurons Contributes to Neurodegeneration with Mitochondria Abnormalities, Reactive Oxygen Species Acceleration and Accumulation of Lipid Droplets in Drosophila Brain

2021 ◽  
Vol 22 (15) ◽  
pp. 8275
Author(s):  
Pavel A. Melentev ◽  
Elena V. Ryabova ◽  
Nina V. Surina ◽  
Darya R. Zhmujdina ◽  
Artem E. Komissarov ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Lipid Droplet ◽  
Hereditary Spastic Paraplegia ◽  
Lipid Droplets ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Spastic Paraplegia ◽  
Swiss Cheese ◽  
Neuron Death

Various neurodegenerative disorders are associated with human NTE/PNPLA6 dysfunction. Mechanisms of neuropathogenesis in these diseases are far from clearly elucidated. Hereditary spastic paraplegia belongs to a type of neurodegeneration associated with NTE/PNLPLA6 and is implicated in neuron death. In this study, we used Drosophila melanogaster to investigate the consequences of neuronal knockdown of swiss cheese (sws)—the evolutionarily conserved ortholog of human NTE/PNPLA6—in vivo. Adult flies with the knockdown show longevity decline, locomotor and memory deficits, severe neurodegeneration progression in the brain, reactive oxygen species level acceleration, mitochondria abnormalities and lipid droplet accumulation. Our results suggest that SWS/NTE/PNPLA6 dysfunction in neurons induces oxidative stress and lipid metabolism alterations, involving mitochondria dynamics and lipid droplet turnover in neurodegeneration pathogenesis. We propose that there is a complex mechanism in neurological diseases such as hereditary spastic paraplegia, which includes a stress reaction, engaging mitochondria, lipid droplets and endoplasmic reticulum interplay.

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