(588.3) Activation of Lysophosphatidic Acid Receptor 3 Promotes Mitochondrial Homeostasis in aged cells

Poster Board Number: E353

Jui-Chung Chiang (University of Texas, Southwestern Medical Center), Wei-Min Chen (University of Texas, Southwestern Medical Center), Hsinyu Lee (National Taiwan University), Benjamin Chen (University of Texas, Southwestern Medical Center)

Lysophosphatidic acid (LPA) is a growth factor-like lipid mediator that regulates various physiological functions via activating multiple G protein-coupled receptors. We previously reported that LPA suppresses oxidative stress in premature aging Hutchinson-Gilford progeria Syndrome (HGPS) patient fibroblasts via its type 3 receptor (LPA3). Mitochondria has been suggested to be the main origin of oxidative stress via overproduction of reactive oxygen species (ROS). Mitochondria is responsible for producing ATP through oxidative phosphorylation (OxPhos) and has calcium buffering capacity for cells. Defects in mitochondria lead to lower antioxidant capacity and lead to apoptosis. Therefore, we aim to investigate the regulatory role of LPA3 in mitochondrial homeostasis. Treatment of LPA3 selective agonist OMPT and siRNA suggest that activation of LPA3 enhances mitochondrial membrane potential (Δψ) and downregulates cellular ROS levels. OMPT treatment increases cellular resistance against OxPhos inhibitors, Rotenone and Antimycin A. In addition, depletion of LPA3 by siRNA results in increasing cisplatin induced cytochrome C releasing. These results indicate that activation of LPA3 is essential to suppress mitochondrial apoptosis. Activation of LPA3 is also shown to promote formation of mitochondria-endoplasmic reticulum contact (MERC) and calcium uptake from ER to mitochondria via IP3R1-VDAC1 channel. On the other hand, activation of LPA3 improves mitochondrial ADP-ATP exchange by enhancing ANT2 expression. Activation of LPA3 rescues mitochondrial homeostasis in HGPS patient fibroblasts through improving Δψ and OxPhos. In conclusion, our findings imply that activation of LPA3 acts as a gatekeeper for mitochondrial healthiness to prevent cell aging. Furthermore, LPA3 may be a promising therapeutic target to prevent mitochondrial oxidative stress in aged cells.

Support or Funding Information

MOST (110-2926-I-002 -509 and 110-2311-B-002 -026) from the Ministry of Science and Technology Taiwan (HL)

National Institutes of Health (CA233594 to BPC), and UTSW Simmons Comprehensive Cancer Center (BPC)

lt;pgt;MOST (110-2926-I-002 -509 and 110-2311-B-002 -026) from the Ministry of Science and Technology Taiwan (HL)lt;/pgt;lt;pgt;National Institutes of Health (CA233594 to BPC), and UTSW Simmons Comprehensive Cancer Center (BPC)lt;/pgt;