Lysophosphatidic Acid Receptor 3 Promotes Mitochondrial Homeostasis against Oxidative Stress: Potential Therapeutic Approaches for Hutchinson-Gilford Progeria Syndrome.

Jui-Chung Chiang,Ciara Newman,Hsinyu Lee,Wei-Min Chen,Benjamin P C Chen

doi:10.3390/antiox11020351

Abstract

Lysophosphatidic acid (LPA) is a growth factor-like lipid mediator that regulates various physiological functions via activation of multiple LPA 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 have been suggested to be the primary origin of oxidative stress via the overproduction of reactive oxygen species (ROS). Mitochondria are responsible for producing ATP through oxidative phosphorylation (OXPHOS) and have a calcium buffering capacity for the cell. Defects in mitochondria will lead to declined antioxidant capacity and cell apoptosis. Therefore, we aim to demonstrate the regulatory role of LPA3 in mitochondrial homeostasis. siRNA-mediated depletion of LPA3 leads to the depolarization of mitochondrial potential (ΔΨm) and cellular ROS accumulation. In addition, the depletion of LPA3 enhances cisplatin-induced cytochrome C releasing. This indicates that LPA3 is essential to suppress the mitochondrial apoptosis pathway. LPA3 is also shown to improve mitochondrial ADP-ATP exchange by enhancing the protein level of ANT2. On the other hand, LPA3 regulates calcium uptake from the ER to mitochondria via the IP3R1-VDAC1 channel. Moreover, activation of LPA3 by selective agonist OMPT rescues mitochondrial homeostasis of H2O2-induced oxidative stress cells and HGPS patient fibroblasts by improving mitochondrial ΔΨm and OXPHOS. In summary, our findings imply that LPA3 acts as the gatekeeper for mitochondrial healthiness to maintain cell youth. Furthermore, LPA3 can be a promising therapeutic target to prevent mitochondrial oxidative stress in aging and HGPS.

Highlights

Introduction iationsLysophosphatidic acid (1- or 2-acyl-sn-glycerol 3-phosphate/radyl-glycerol-phosphate, LPA) is a bioactive lipid mediator produced both intracellularly and extracellularly from membrane phospholipids and is detected robustly in all eukaryotic tissues and blood plasma [1]
To delineate the role of LPA3 and its underlying mechanism in regulating mitochondrial activity, we subjected the Small interfering RNA (siRNA) control and LPA3 siRNA-treated human cervical cancer HeLa cells to a cell proliferation assay with electron transport chain (ETC) complex I
LPA3 siRNA knockdown cells were susceptible to the two ETC inhibitors, suggesting that that LPA3 was required to counter mitochondrial stress

Summary

Introduction

Introduction iationsLysophosphatidic acid (1- or 2-acyl-sn-glycerol 3-phosphate/radyl-glycerol-phosphate, LPA) is a bioactive lipid mediator produced both intracellularly and extracellularly from membrane phospholipids and is detected robustly in all eukaryotic tissues and blood plasma [1]. LPA evokes various cellular responses by activating six distinct G proteincoupled receptors (GPCRs) localized in the plasma membrane of various cells, mediating cell proliferation, migration, and cytoskeletal reorganization [2]. These receptors are subdivided into the endothelial cell differentiation gene family (Edg, LPA1 -LPA3 ) [3] and the. P2Y purinergic receptor family (LPA4 -LPA6 ) [4]. Upon binding with LPA, conformational changes of LPA receptors allow them to act as guanine nucleotide exchange factors for one or more of the four classes of heterotrimeric G proteins, G12/13 , Gq/11 , Gi/o , and Gs , which.

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