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- Title
Megalin mediates plasma membrane to mitochondria cross-talk and regulates mitochondrial metabolism.
- Authors
Li, Qingtian; Lei, Fan; Tang, Yi; Pan, Jenny Szu-Chin; Tong, Qiang; Sun, Yuxiang; Sheikh-Hamad, David
- Abstract
Mitochondrial intracrines are extracellular signaling proteins, targeted to the mitochondria. The pathway for mitochondrial targeting of mitochondrial intracrines and actions in the mitochondria remains unknown. Megalin/LRP2 mediates the uptake of vitamins and proteins, and is critical for clearance of amyloid-β protein from the brain. Megalin mutations underlie the pathogenesis of Donnai-Barrow and Lowe syndromes, characterized by brain defects and kidney dysfunction; megalin was not previously known to reside in the mitochondria. Here, we show megalin is present in the mitochondria and associates with mitochondrial anti-oxidant proteins SIRT3 and stanniocalcin-1 (STC1). Megalin shuttles extracellularly-applied STC1, angiotensin II and TGF-β to the mitochondria through the retrograde early endosome-to-Golgi transport pathway and Rab32. Megalin knockout in cultured cells impairs glycolytic and respiratory capacities. Thus, megalin is critical for mitochondrial biology; mitochondrial intracrine signaling is a continuum of the retrograde early endosome-to-Golgi-Rab32 pathway and defects in this pathway may underlie disease processes in many systems.
- Subjects
MEGALIN; CELL membranes; MITOCHONDRIA; CELL cycle proteins; AMYLOID beta-protein
- Publication
Cellular & Molecular Life Sciences, 2018, Vol 75, Issue 21, p4021
- ISSN
1420-682X
- Publication type
Article
- DOI
10.1007/s00018-018-2847-3