Study of lipophagy mediated by two-pore channels receptors

Abstract

Metabolic diseases related to obesity are a major public health issue worldwide. Lipids are essential components of a cell providing energy substrates for cellular processes, signaling intermediates, and building blocks of biological membranes. Lysosomes play an important role in this recycling process that involves the recruitment of lipids to lysosomes via autophagy for their degradation by lysosomal lipases. This process, called lipophagy, ca be regulated by the transcription factor EB (TFEB), the master regulator of autophagy, can be functionally activated by lysosomal Ca2+ release in response to alteration of metabolism. The nicotinic acid adenine dinucleotide phosphate (NAADP) has been reported as an important second messenger via the Two-Pore Channels (TPC1 and TPC2 isoforms) located in the endolysosomal system. The TPC activation by NAADP leads to the Ca2+ release from lysosomes activating autophagy and vesicular traffic. However, these mechanisms must be further investigated. In this project, we focus on this relationship in the context of lipophagy and provide new evidences of how lipotoxicity can be regulated. Experiments to evaluate the pathways related to autophagic flux, TFEB signaling and metabolism will be performed in adipocytes from brown adipose tissue in the presence or absence of NAADP, overexpressing or silencing Tpcn genes. Using confocal and electron microscopy will evaluate the morphology and functionality of autophagossomes and lysosomes. Thus, this study highlights the importance of TPC-mediated autophagy in the physiopathology of obesity, which can add knowledge to contribute for the development of new therapies. (AU)