title: Association of LETM1 and MRPL36 contributes to the regulation of mitochondrial ATP production and necrotic cell death.
abstract: Leucine zipper/EF hand-containing transmembrane-1 (LETM1) is a mitochondrial inner membrane protein that was first identified in Wolf-Hirschhorn syndrome, and was deleted in nearly all patients with the syndrome. LETM1 encodes for the human homologue of yeast Mdm38p, which is a mitochondria-shaping protein of unclear function. Here, we describe LETM1-mediated regulation of mitochondrial ATP production and biogenesis. We show that LETM1 overexpression can induce necrotic cell death in HeLa cells, in which LETM1 reduces mitochondrial biogenesis and ATP production. LETM1 acts as an anchor protein and associates with mitochondrial ribosome protein L36. Adenovirus-mediated overexpression of LETM1 reduced mitochondrial mass and expression of many mitochondrial proteins. LETM1-mediated inhibition of mitochondrial biogenesis enhanced glycolytic ATP supply and activated protein kinase B activity and cell survival signaling. The expression levels of LETM1 were significantly increased in multiple human cancer tissues compared with normals. These data suggest that LETM1 serves as an anchor protein for complex formation with the mitochondrial ribosome and regulates mitochondrial biogenesis. The increased expression of LETM1 in human cancer suggests that dysregulation of LETM1 is a key feature of tumorigenesis.
authors.affiliation: Department of Pharmacology, Daejeon Regional Cancer Center, Cancer Research Institute, Research Institute for Medical Sciences, South Korea.
authors.forename: Longzhen
authors.initials: L
authors.lastname: Piao
authors.forename: Yuwen
authors.initials: Y
authors.lastname: Li
authors.forename: Soung Jung
authors.initials: SJ
authors.lastname: Kim
authors.forename: Hee Sun
authors.initials: HS
authors.lastname: Byun
authors.forename: Song Mei
authors.initials: SM
authors.lastname: Huang
authors.forename: Soon-Kyung
authors.initials: SK
authors.lastname: Hwang
authors.forename: Keum-Jin
authors.initials: KJ
authors.lastname: Yang
authors.forename: Kyeong Ah
authors.initials: KA
authors.lastname: Park
authors.forename: Minho
authors.initials: M
authors.lastname: Won
authors.forename: Janghee
authors.initials: J
authors.lastname: Hong
authors.forename: Gang Min
authors.initials: GM
authors.lastname: Hur
authors.forename: Jeong Ho
authors.initials: JH
authors.lastname: Seok
authors.forename: Minho
authors.initials: M
authors.lastname: Shong
authors.forename: Myung-Haing
authors.initials: MH
authors.lastname: Cho
authors.forename: Derek P
authors.initials: DP
authors.lastname: Brazil
authors.forename: Brian A
authors.initials: BA
authors.lastname: Hemmings
authors.forename: Jongsun
authors.initials: J
authors.lastname: Park