Lipids associated with autophagy: mechanisms and therapeutic targets

Abstract

Autophagy is a molecular process essential for maintaining cellular homeostasis, with its impairment or dysregulation linked to the progression of various diseases in mammals. Specific lipids, including phosphoinositides, sphingolipids, and oxysterols, play pivotal roles in inducing and regulating autophagy, highlighting their significance in this intricate process. This review focuses on the critical involvement of these lipids in autophagy and lipophagy, providing a comprehensive overview of the current understanding of their functions. Moreover, we delve into how abnormalities in autophagy, influenced by these lipids, contribute to the pathogenesis of various diseases. These include age-related conditions such as cardiovascular diseases, neurodegenerative disorders, type 2 diabetes, and certain cancers, as well as inflammatory and liver diseases, skeletal muscle pathologies and age-related macular degeneration (AMD). This review aims to highlight function of lipids and their potential as therapeutic targets in treating diverse human pathologies by elucidating the specific roles of phosphoinositides, sphingolipids, and oxysterols in autophagy.

Fig. 1. Schematic overview of autophagy induction with a focus on lipid involvement in signaling regulation.

mTORC1, a key suppressor of autophagy, is inhibited by AMPK under conditions promoting autophagy. AMPK also activates the ULK1/2 complex, which consists of ULK1/2, Atg13, FIP200, and Atg101. Upon activation, the ULK1/2 complex stimulates the PI3KC3 complex I, composed of VPS15, Beclin1, VPS34, and ATG14L. This complex regulates the production of phosphatidylinositol-3-phosphate (PI3P) on the phagophore, a crucial lipid that signals the progression of autophagy. Further downstream, lipids play an essential role in conjugating phosphatidylethanolamine (PE) to LC3, facilitating the formation of the autophagosome. The conjugation of LC3 with PE ensures membrane expansion and curvature necessary for autophagosome maturation, emphasizing the critical roles of lipids in both signal propagation and structural development during autophagy.

Fig. 2. Schematic overview of the major steps of autophagy with a focus on lipid involvement.

Atg proteins bind to PI3P on the phagophore surface, initiating the process. The Atg9-Atg2-Atg18 complex mediates lipid transfer from the ER to the growing phagophore, facilitating its elongation. Lipids play a critical role in regulating autophagy signaling at this stage. SQSTM1, with preselected cargo attached, binds to LC3-PE on the inner surface of the forming autophagosome. During autophagosome maturation, MTMR3 dephosphorylates PI3P, leading to the dissociation of Atg proteins, which is crucial for the autophagosome to become fusion-competent. Finally, lysosomes fuse with the matured autophagosome to form an autolysosome, where lipids and other cellular components undergo degradation in the final phase of autophagy.