Role of mitochondria-associated endoplasmic reticulum membranes in lipid droplet formation – MADE

Non-vesicular lipid transport mediated by lipid transfer proteins (LTPs) at membrane contact sites (MCS) is emerging as a key mechanism to preserve the membrane identity of cellular organelles, especially in the case of mitochondria (Mito) and Lipid droplets (LDs) that are not integrated into the classical vesicular routes. Mitochondria (key for energy production) and LDs (cellular reserve of energy) are essential for cellular homeostasis/bioenergetics and their functions require a constant and regulated exchange of lipids with the Endoplasmic Reticulum (ER), the major site of lipid synthesis, through MCS. Specific lipid biosynthetic activities are enriched at ER subdomains in contact with mitochondria called Mitochondria Associated ER Membranes (MAMs). However how lipids are shuttled at ER-Mito and ER-LDs MCS is still largely unknown. Also, how and where LDs originate from the ER is still unclear. Our multidisciplinary project aims to characterize the role of a novel Mito-MAM-LD MCS association in non-vesicular lipid trafficking and LD biogenesis by studying the role of two LTPs, recently found by our group to localize at these MCS. Understanding the role of ORP5/8 at the Mito-MAM-LD connection will have a major impact not only in the lipid trafficking and in the MCS field, but also, in a long term, on our understanding of the pathophysiological mechanisms of various diseases where MAMs and LD functions are affected, including Alzheimer’s.