Abstract
The multi-ligand binding protein megalin (LRP2) is ubiquitously expressed and facilitates cell uptake of hormones, nutrients and vitamins. We have recently shown megalin is present in the mitochondria of cultured epithelial and mesenchymal cells, as well as many organs and tissues. Mitochondrial megalin associates with stanniocalcin-1 and SIRT3; two proteins that promote anti-oxidant defenses. Megalin shuttles mitochondrial intracrines (angiotensin II, stanniocalcin-1 and TGF-β) from the cell surface to the mitochondria through the retrograde early endosome to Golgi pathway and requires Rab32. Deletion of megalin impairs mitochondrial respiration and glycolysis. This pathway overlaps molecular and vesicular trafficking defects common to Donai Barrow and Lowe syndromes, suggesting that mitochondrial intracrine signaling defects may contribute to the pathogenesis of these diseases.
Highlights
Low-molecular weight proteins, cofactors, amino acids, metabolites and many bioactive signaling molecules are filtered through the glomeruli
We will briefly discuss some aspects of megalin’s functions and expand on the role of megalin in facilitating mitochondrial intracrine signaling
Similar neurological developmental abnormalities are observed in humans with autosomal recessive Donnai-Barrow and facio-oculoacoustico-renal (DB/FOAR) syndrome where various loss-offunction mutations in LRP2 result in corpus callosum agenesis, in addition to ocular, hearing, and facial abnormalities accompanied by low-molecular weight proteinuria [4]
Summary
Megalin-Mediated Trafficking of Mitochondrial Intracrines: Relevance to Signaling and Metabolism.
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