Association of LETM1 and MRPL36 contributes to the regulation of mitochondrial ATP production and necrotic cell death.

[wolf-hirschhorn syndrome]

Leucine zipper /EF hand -containing transmembrane-1 (LETM 1 ) is a mitochondrial inner membrane protein that was first identified in Wolf-Hirschhorn syndrome , and was deleted in nearly all patients with the syndrome . LETM 1 encodes for the human homologue of yeast Mdm 38 p , which is a mitochondria-shaping protein of unclear function . Here , we describe LETM 1 -mediated regulation of mitochondrial ATP production and biogenesis . We show that LETM 1 overexpression can induce necrotic cell death in HeLa cells , in which LETM 1 reduces mitochondrial biogenesis and ATP production . LETM 1 acts as an anchor protein and associates with mitochondrial ribosome protein L 36 . Adenovirus-mediated overexpression of LETM 1 reduced mitochondrial mass and expression of many mitochondrial proteins . LETM 1 -mediated inhibition of mitochondrial biogenesis enhanced glycolytic ATP supply and activated protein kinase B activity and cell survival signaling . The expression levels of LETM 1 were significantly increased in multiple human cancer tissues compared with normals . These data suggest that LETM 1 serves as an anchor protein for complex formation with the mitochondrial ribosome and regulates mitochondrial biogenesis . The increased expression of LETM 1 in human cancer suggests that dysregulation of LETM 1 is a key feature of tumorigenesis .