Met-HGF/SF Signal Transduction Induces Mimp, a Novel Mitochondrial Carrier Homologue, Which Leads to Mitochondrial Depolarization

Abstract

Met-hepatocyte growth factorlscatter factor (HGFJSF) signaling plays an important role in epithelial tissue morphogenesis, lumen formation, tumorigenicity. We have recently demonstrated that HGFJSF also alters the metabolic activity of cells by enhancing both the glycolytic and oxidative phosphorylation pathways of energy production. Using differential display polymerase chain reaction, we cloned a novel gene, designated mimp (Met-Induced Mitochondrial Protein), which is upregulated in NIH-3T3 cells cotransfected with both HGFISFand Met (HMH cells). Northern and Western blot analyses showed that mime is induced in several Metexpressing cell lines following treatment with HGFJSF. Mimp encodes a 33-kDa protein that shows sequence homology to the family of mitochondrial carrier proteins (MCPs). Murine Mimp (mMimp) is expressed in a wide variety of tissues., exhibiting an expression pattern similar to Met. Predominant expression is seen in liver, kidney, heart, skeletal muscle, testis. Using immunostaining for HA-tagged mMimp and a GFP-mMimp chimeric protein as well as subcellular fractionation, we determined that Mimp is primarily localized to the mitochondria. Ectopic expression of mMimp in the Met-responsive adenocarcinoma cell line, DA3, reduced the mitochondrial membrane potential (uncoupling activity). The extent of the mitochondrial depolarization positively correlated with the level of Mimp expression. Our results demonstrate that Mimp is a novel mitochondrial carrier homologue upregulated by Met-HGFJSF signal transduction, which leads to mitochondrial depolarization, suggest novel links among tyrosine kinase signaling, mitochondrial function, cellular bmenergetics.

Keywords

• Met
• HGF/SF
• tyrosine kinase growth tactor receptor
• metochondrial potential sampling