https://orcid.org/0000-0002-7828-8118
ABSTRACT
Autophagy, in the form of lipophagy, is an important catabolic pathway mediating the degradation of lipid droplets and mobilization of lipids for physiological function. However, the molecular mechanism and the protein receptors that link lipid droplets/LDs to the autophagy machinery remain unknown. Here, we discuss a recent study by Chung et al. that identifies SPART as the receptor for autophagy of lipid droplets that plays an important role in the turnover of triglycerides in motor neurons.
Lipid metabolism is a fundamental process that is crucial for biological pathways such as energy storage, mediators of signaling, and biogenesis of cellular membranes [Citation1]. Long regarded as superficial cytoplasmic lipid deposits, lipid droplets have become pivotal subcellular entities [Citation2]. Ubiquitous across diverse cellular contexts, lipid droplets serve as dynamic hubs, maintaining lipid homeostasis and adapting to the dynamic metabolic necessities of the cell. Perturbations to lipid storage have been implicated in diverse pathological conditions such as obesity, inflammation, neurodegenerative diseases, and cancer. Therefore, maintaining appropriate levels of lipids in the appropriate context in the cell is imperative for normal functioning [Citation3].
Cells employ two main strategies to mobilize lipids from lipid droplets: lipolysis and lipophagy. Lipolysis consists of a series of hydrolytic reactions initiated by hydrolases, whereas lipophagy involves the selective delivery of lipid droplets to lysosomes for degradation by lysosomal acid lipases. While the importance of lipophagy in maintaining cellular homeostasis is established, the molecular mechanisms and the protein receptors that link autophagy machinery to lipid droplets are yet to be elucidated [Citation3].
Towards addressing this question, Chung et al. hypothesized that the protein SPART/SPG20 (spartin) could serve as the receptor for lipophagy owning to its localization to lipid droplets and the presence of ubiquitin-binding regions, a domain shared by other selective autophagy receptors such as SQSTM1/p62 [Citation4]. In investigating this hypothesis, Chung et al. determined that SPART localizes to mature lipid droplets containing less PLIN3, which is localized to the cell periphery. Furthermore, upon oleic acid withdrawal, SPART increases its association with the autophagy machinery and lysosomes via MAP1LC3/LC3 proteins and LAMP1, respectively. Structural analysis of SPART shows the preservation of the ubiquitin-binding region/UBR domain that contains an LC3-interesting region/LIR, which mediates the interaction of SPART and LC3.
In order to measure the effect of SPART on lipophagy, Chung et al. developed a lipophagy reporter assay using a pH-sensitive Keima fluorophore that attaches to lipid droplets. Upon oleic acid withdrawal, they observed that SPART-tagged lipid droplets are delivered to the lysosome by observing pH-sensitive changes in the excitation spectrum of the reporter. Consistently, the deletion of SPART significantly lowers the clearance of lipid droplets. Finally, the authors show that disruption of SPART in murine neurons in the motor cortex leads to the accumulation of triglycerides in lipid droplets. This finding indicates the important role played by SPART in mediating the turnover of triglycerides in the mouse brain.
Together, Chung et al. provide concise evidence that SPART is involved in the turnover of lipid droplets by linking them to the autophagy machinery. Furthermore, its role in lipophagy in neurons has solid implications for Troyer syndrome, a disease wherein SPART is mutated. Studies aimed at understanding the role of lipophagy in Troyer syndrome will increase our understanding of the importance of lipid homeostasis in motor neurons [Citation4].
This study paves the way to several important questions in the field of lipophagy. What is the importance of SPART associating with only a subpopulation of lipid droplets? Are there different lipophagy receptors for nascent and mature droplets? Furthermore, are there cell-specific lipophagy receptors or does SPART play a universal role as a lipophagy receptor? What is the role of SPART in neurodegeneration? Further investigation may provide better understanding for the role of the turnover of lipid droplets and its implications in neurodegenerative diseases.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Additional information
Funding
References
- Olzmann JA, Carvalho P. Dynamics and functions of lipid droplets. Nat Rev Mol Cell Biol. 2019;20(3):137–155. doi: 10.1038/s41580-018-0085-z
- Farese RV Jr., Walther TC. Lipid droplets finally get a little R-E-S-P-E-C-T. Cell. 2009;139(5):855–860. doi: 10.1016/j.cell.2009.11.005
- Zhang S, Peng X, Yang S, et al. The regulation, function, and role of lipophagy, a form of selective autophagy, in metabolic disorders. Cell Death Dis. 2022;13(2):132. doi: 10.1038/s41419-022-04593-3
- Chung J, Park J, Lai ZW, et al. The Troyer syndrome protein spartin mediates selective autophagy of lipid droplets. Nat Cell Biol. 2023;25(8):1–10. doi: 10.1038/s41556-023-01178-w