Megalin mediates plasma membrane to mitochondria cross-talk and regulates mitochondrial metabolism. Academic Article uri icon


  • 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- 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- 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.

published proceedings

  • Cell Mol Life Sci

altmetric score

  • 0.25

author list (cited authors)

  • Li, Q., Lei, F., Tang, Y. i., Pan, J., Tong, Q., Sun, Y., & Sheikh-Hamad, D.

citation count

  • 18

complete list of authors

  • Li, Qingtian||Lei, Fan||Tang, Yi||Pan, Jenny Szu-Chin||Tong, Qiang||Sun, Yuxiang||Sheikh-Hamad, David

publication date

  • January 2018