Francesca Giordano
“Ménage à trois”: role of endoplasmic reticulum-mitochondria contact sites in lipid droplet biogenesis and implication in Alzheimer’s disease
Abstract: Mitochondria (Mito, key for energy production) and lipid droplets (LD, cellular reserve of energy) are essential for cellular homeostasis/bioenergetics. To preserve their morphological and functional identities Mito and LD require a constant and regulated exchange of lipids with the endoplasmic reticulum (ER), major cellular site of lipid synthesis, via membrane contact sites (CS). However, how lipids are shuttled between these organelles and how/where LD originate from the ER is still unclear. Also, dysfunctions of Mito and LD are associated with the pathophysiology of many neurodegenerative disorders such as Alzheimer’s disease (AD). However, how such dysfunctions are established and whether they are functionally connected, remain mysterious. We have recently shown that ER subdomains that contact mitochondria or Mito-Associated Membranes (MAM) are hotspots for LD biogenesis, revealing the existence of a novel tripartite association between Mito, ER and nascent LD. We have found that two lipid transfer proteins ORP5 and ORP8 localize to MAM subdomains where LD originate and that their depletion decreases LD biogenesis in HeLa cells and human hepatocytes. We have also found that ORP5 interacts with seipin, a master regulator of LD biogenesis, and modulates its targeting to MAM-LD contacts. We hypothesize that MAM could play a key role in mediating Mito-LD crosstalk in health and in neurodegeneration. We propose that the early cellular dysfunctions associated to AD involving Mito and LD could be all orchestrated by the MAM. We are currently investigating the function of ORP5/ORP8 and of their binding partners in lipid transfer and storage at MAM-LD contact sites as well as the morphology and remodelling of these contact sites in multiple cell lines including models of AD. Our studies aim to brings novel insights into the metabolic crosstalk between Mito, ER, and LD at membrane contact sites and their implication in neurodegeneration.
