Abstract
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.
Highlights
Lipid droplets (LDs) are cytosolic organelles specialized in storing neutral lipids such as triacylglycerols (TAGs) and cholesterol esters
Biogenesis of LDs occurs de novo from the tubular ER and follows distinct steps, beginning with the accumulation of neutral lipids between the two leaflets of the ER membrane to form a lens-like structure that progressively grows into nascent LDs that expand into mature LDs (Pol et al, 2014; Walther et al, 2017)
Upon oleic acid (OA) addition, spastin-M1 is recovered in the LD fraction in NCS34 cells (Papadopoulos et al, 2015)
Summary
Lipid droplets (LDs) are cytosolic organelles specialized in storing neutral lipids such as triacylglycerols (TAGs) and cholesterol esters. LDs segregate a lipid core within a phospholipid monolayer coated with specific proteins and play crucial roles by protecting cells from lipotoxicity, serving as energy reservoirs, forming compartments for protein storage or degradation, and mediating lipid trafficking between organelles and membranes (Listenberger et al, 2003; Cermelli et al, 2006; Zehmer et al, 2009; Moldavski et al, 2015; Schuldiner & Bohnert, 2017). Connections between the ER and the LDs are crucial to allow some enzymes involved in the last step of TAG synthesis to relocalize from the ER to LDs (Wilfling et al, 2013). LDs interact with other organelles such as mitochondria, peroxisomes, and lysosomes (Schuldiner & Bohnert, 2017)
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