Association of LETM1 and mrpl36 contributes to the regulation of mitochondrial ATP production and necrotic cell death

Longzhen Piao*, Yuwen Li, Soung Jung Kim, Hee Sun Byun, Song Mei Huang, Soon Kyung Hwang, Keum Jin Yang, Kyeong Ah Park, Minho Won, Janghee Hong, Gang Min Hur, Jeong Ho Seok, Minho Shong, Myung Haing Cho, Derek P. Brazil, Brian A. Hemmings, Jongsun Park

*Corresponding author for this work

Research output: Contribution to journalArticle

49 Citations (Scopus)

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 overexpres-sion 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. LETMl-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.

Original languageEnglish
Pages (from-to)3397-3404
Number of pages8
JournalCancer Research
Volume69
Issue number8
DOIs
Publication statusPublished - 15 Apr 2009

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Piao, L., Li, Y., Kim, S. J., Byun, H. S., Huang, S. M., Hwang, S. K., Yang, K. J., Park, K. A., Won, M., Hong, J., Hur, G. M., Seok, J. H., Shong, M., Cho, M. H., Brazil, D. P., Hemmings, B. A., & Park, J. (2009). Association of LETM1 and mrpl36 contributes to the regulation of mitochondrial ATP production and necrotic cell death. Cancer Research, 69(8), 3397-3404. https://doi.org/10.1158/0008-5472.CAN-08-3235