Association of LETM1 and MRPL36 Contributes to the Regulation of Mitochondrial ATP Production and Necrotic Cell Death

• Published in: Cancer research (Chicago, Ill.) Ill.), 2009-04, Vol.69 (8), p.3397-3404
• Main Authors: LONGZHEN PIAO, YUWEN LI, GANG MIN HUR, JEONG HO SEOK, SHONG, Minho, CHO, Myung-Haing, BRAZIL, Derek P, HEMMINGS, Brian A, PARK, Jongsun, SOUNG JUNG KIM, HEE SUN BYUN, SONG MEI HUANG, HWANG, Soon-Kyung, YANG, Keum-Jin, KYEONG AH PARK, WON, Minho, HOG, Janghee
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - biosynthesis; Antineoplastic agents; Biological and medical sciences; Calcium-Binding Proteins - biosynthesis; Calcium-Binding Proteins - metabolism; Cell Death - physiology; Enzyme Activation; HeLa Cells; Humans; Lactic Acid - metabolism; Medical sciences; Membrane Proteins - biosynthesis; Membrane Proteins - metabolism; Mitochondria - metabolism; Mitochondrial Proteins - metabolism; Necrosis; Oxygen Consumption; Pharmacology. Drug treatments; Proto-Oncogene Proteins c-akt - metabolism; Ribosomal Proteins - metabolism; Signal Transduction; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-08-3235

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.