Research Projects

MTCH2 encodes an outer mitochondrial membrane protein. Several genome-wide association studies have revealed a strong link between MTCH2 and metabolic disorders including obesity and diabetes. In mice, loss of MTCH2 protects from diet-induced obesity. However, the mechanism by which MTCH2 contributes to these diseases is not clearly understood. Previously we have reported stop codon readthrough (SCR) of MTCH2 in mammalian cells. Using genetically modified cell lines (RTnull-MTCH2 cells), we have demonstrated that SCR of MTCH2 is required to maintain normal mitochondrial membrane potential, and therefore normal cellular ATP levels. In the current proposal, we plan to continue this study in a mouse model to understand the in vivo significance of SCR of MTCH2 mRNA. We have already generated (through Cyagen, Inc) genetically modified mice, which don’t show SCR of MTCH2 (RTnull-MTCH2 mice). Objective 1. We will investigate multiple physiological parameters that are influenced by mitochondrial dysfunction such as blood glucose level, blood pressure, lipid profile and liver function. At cellular level we will measure ATP production, reactive oxygen species and mitochondrial mass. Their levels will be compared between wild-type and RTnull-MTCH2 mice under normal diet and high-fat diet. Based on our previous study in cell lines, we expect to observe metabolic dysfunction in RTnull-MTCH2 mice caused by mitochondrial dysfunction. Objective 2. In this objective, we plan to understand the molecular mechanism by which SCR of MTCH2 affects mitochondrial function. We will use cells derived from RTnull-MTCH2 mice and also genetically modified cell lines for this purpose. We plan to investigate the expression (transcriptional and post-transcriptional levels) and function of mitochondrial oxidative phosphorylation system (OXPHOS, Complex 1 to V). Mitochondrial morphology and mitochondrial translation will also be probed in these genetically modified mice. After the end of the project, we will know how SCR of MTCH2 contributes to, or protects from, metabolic diseases such as obesity and diabetes. We will also learn the cellular and molecular events in this process. This information will provide us new molecular targets for the management of these diseases.