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Abstract: PO1929

LRP2-Facilitated Regulation of Mitochondrial Metabolism by Extracellular Cues: Important Roles for Signal Peptides' Leucines in Protein-Protein Interactions and Signaling

Session Information

Category: Pathology and Lab Medicine

  • 1600 Pathology and Lab Medicine

Authors

  • Li, Qingtian, Baylor College of Medicine, Houston, Texas, United States
  • Holliday, Michael, Baylor College of Medicine, Houston, Texas, United States
  • Pan, Jenny S., Baylor College of Medicine, Houston, Texas, United States
  • Tan, Li, Sichuan University West China Medical Center, Chengdu, Sichuan, China
  • Li, Jeffery, Baylor College of Medicine, Houston, Texas, United States
  • Sheikh-Hamad, David, Baylor College of Medicine, Houston, Texas, United States
Background

Stanniocalcin 1 (STC1), a mitochondrial intracrine activates mitochondrial anti-oxidant defenses. LRP2/megalin shuttles STC1 to the mitochondria through retrograde early endosome-to-Golgi- and Rab32, and LRP2 KO impairs mitochondrial respiration and glycolysis.

Methods

We determined STC1-LRP2 interaction domains using HA- and FLAG-tagged fragments of STC1 and LRP2, respectively, co-expressed in HEK293T cells.

Results

The trans-membrane domain of LRP2 is required for trafficking to the mitochondria. STC1-FLAG expressed in LRP2 KO cells fails to reach the mitochondria; thus, mitochondrial STC1 is extracellularly-derived via LRP2-mediated trafficking. Tri-leucines L12-14 in LRP2’s signal peptide interact with STC1’s signal peptide. Mutant LRP2 (L12-L14 -> A12-14) does not bind STC1, while hSTC1 lacking signal peptide or Leucines L8/9/11 does not bind LRP2. Using Seahorse analyzer, STC1 fails to induce respiration or glycolysis in megalin KO MEF expressing mutant LRP2, while mutant hSTC1 (L8/L9/L11 -> A8/A9/A11) fails to reach the mitochondria or induce respiration and glycolysis in WT MEF.

Conclusion

Our data suggest direct regulation of mitochondrial metabolism by extracellular cues and reveal an important role for signal peptides and their leucines in protein-protein interactions and signaling.

Graphic abstract

Funding

  • Veterans Affairs Support