Comparative Gene Identification-58 (CGI-58) Promotes Autophagy as a Putative Lysophosphatidylglycerol Acyltransferase [Metabolism]

October 14th, 2014 by Zhang, J., Xu, D., Nie, J., Han, R., Zhai, Y., Shi, Y.

CGI-58 is a lipid droplet-associated protein when mutated causes Chanarin-Dorfman syndrome in humans, which is characterized by excessive storage of triglyceride (TAG) in various tissues. However, the molecular mechanisms underlying the defect remain elusive. CGI-58 was previously reported to catalyze the resynthesis of phosphatidic acid (PA) as a lysophosphatidic acid acyltransferase. In addition to TAG, PA is also used a substrate for the synthesis of various mitochondrial phospholipids. In this report, we investigated the propensity of CGI-58 in the remodeling of various phospholipids. We found that the recombinant CGI-58 overexpressed in mammalian cells or purified from Sf9 insect cells catalyzed efficiently the reacylation of lysophosphatidylglycerol to phosphatidylglycerol (PG), which requires acyl-CoA as the acyl donor. In contrast, the recombinant CGI-58 was devoid of acyltransferase activity towards other lysophospholipids. Accordingly, overexpression and knockdown of CGI-58 adversely affected the endogenous PG level in C2C12 cells. PG is a substrate for the synthesis of cardiolipin which is required for mitochondrial oxidative phosphorylation and mitophagy. Consequently, overexpression and knockdown of CGI-58 adversely affected autophagy and mitophagy in C2C12 cells. In support for a key role of CGI-58 in mitophagy, overexpression of CGI-58 significantly stimulated mitochondrial fission and translocation of PINK1 to mitochondria, key steps involved in mitophagy. Furthermore, overexpression of CGI-58 promoted mitophagic initiation through activation of AMPK and inhibition of mTORC1 signaling, the positive and negative regulators of autophagy, respectively. Together, these findings identified novel molecular mechanisms by which CGI-58 regulates lipid homeostasis, since defective autophagy is implicated in dyslipidemia and fatty liver diseases.