title: TMEM14A inhibits N-(4-hydroxyphenyl)retinamide-induced apoptosis through the stabilization of mitochondrial membrane potential.
abstract: Apoptosis is a highly conserved genetic process leading to death in mammalian cells. A critical step in apoptosis is mitochondrial membrane permeabilization, which results in the release of proteins critical to downstream events. Transmembrane protein 14A (TMEM14A) was identified as a novel suppressor of Bax using yeast-based functional screening. TMEM14A is a novel mitochondria-associated membrane protein containing a putative transmembrane domain. Over-expression of TMEM14A in U87MG cells inhibited N-(4-hydroxyphenyl)retinamide (4-HPR)-induced apoptosis. TMEM14A prevented 4-HPR-induced loss of mitochondrial membrane potential (MMP), the release of cytochrome c, and the activation of caspase-3, but not the generation of reactive oxygen species, suggesting that TMEM14A regulates mitochondrial membrane potential in a ROS-independent manner. As expected, cyclosporin A, an inhibitor of membrane potential transition, inhibited 4-HPR-induced loss of MMP and apoptosis in U87MG cells, indicating that loss of MMP plays a pivotal role in 4-HPR-induced apoptosis. Suppression of TMEM14A expression using shRNA significantly increased apoptosis and MMP loss in untreated and 4-HPR-treated cells. These findings show for the first time that TMEM14A inhibits apoptosis by blocking the mitochondrial permeability transition and stabilizing mitochondrial membrane potential.
authors: Department of Pharmacology, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 660-751, Republic of Korea.
authors: Im Sun
authors: IS
authors: Woo
authors: Hana
authors: H
authors: Jin
authors: Eun Sil
authors: ES
authors: Kang
authors: Hye Jung
authors: HJ
authors: Kim
authors: Jae Heun
authors: JH
authors: Lee
authors: Ki Churl
authors: KC
authors: Chang
authors: Jae-Yong
authors: JY
authors: Park
authors: Wan Sung
authors: WS
authors: Choi
authors: Han Geuk
authors: HG
authors: Seo
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D016572:Cyclosporine / Q000378:metabolism; D045304:Cytochromes c / Q000096:biosynthesis; D004791:Enzyme Inhibitors; D017313:Fenretinide / Q000378:metabolism / Q000494:pharmacology*; D005434:Flow Cytometry; D005909:Glioblastoma; D006801:Humans; D015151:Immunoblotting; D053078:Membrane Potential, Mitochondrial; D008565:Membrane Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000502:physiology; D034622:RNA Interference; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C494826:BAX protein, human; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C561462:TMEM14A protein, human; D051028:bcl-2-Associated X Protein; D017313:Fenretinide; D016572:Cyclosporine; D045304:Cytochromes c; D053148:Caspase 3