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

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 (∆Ψm) 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 H₂ O₂-induced oxidative stress cells and HGPS patient fibroblasts by improving mitochondrial ∆Ψm 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.