Megalin Facilitates the Regulation of Mitochondrial Function by Extracellular Cues

Abstract

Megalin (also known as low density lipoprotein-receptor related protein 2 [LRP2]) is a multi-ligand cell-surface endocytic receptor expressed widely; it is important for the uptake of vitamins, nutrients and hormones. We recently reported the discovery of LRP2/megalin in the mitochondria of many cells and organs. Importantly, megalin traffics the mitochondrial intracrines stanniocalcin-1, TGF-β and angiotensin II from the extracellular milieu to the mitochondria. This transport parallels the retrograde early endosome to Golgi pathway and requires the Rab GTPase Rab32 in the mitochondria, megalin associates with sirtuin family of class III histone deacetylases (Sirt3) and stanniocalcin-1 (Stc1), which are important for anti-oxidant defenses. Deletion of megalin impairs mitochondrial respiration and glycolysis. The interaction between stanniocalcin-1 and megalin is mediated by leucines within the signal peptides of the proteins; and this interaction is essential to the stimulation of mitochondrial respiration and glycolysis by stanniocalcin-1. Our findings suggest that megalin facilitates the regulation of mitochondrial function by extracellular cues.