Grant: Project Grant

When cellular metabolism is improperly regulated, it can lead to various diseases. One specific form of metabolic dysfunction arises from abnormalities in membranes adjacent to mitochondria, where key metabolic regulators are concentrated. These membranes are called mitochondria-associated membranes (MAMs). MAMs control mitochondrial energy production and glycolysis. MAMs protein mutations cause hereditary diseases with shared characteristics, including abnormal brain development, and seizures. Despite the genetic diversity underlying these diseases, the reason for their remarkable similarity remains unknown. We have approached this puzzling finding by focusing on enzymes that control oxidation of proteins found on MAMs. These enzymes control the readout of oxidative stress on mitochondrial function, which can have beneficial effects by enhancing mitochondrial energy production. However, excessive oxidative stress can trigger a series of events leading to cellular and organ dysfunction. In our current study, we focus on the enzyme TMX2, which is an oxidative stress controller at MAMs. Mutations in TMX2 cause a classic MAMs genetic disorder with abnormal brain development and seizures. Our project utilizes both in vitro and in vivo approaches to comprehensively explore the functions of TMX2. In preliminary data, we delineate the molecular mechanisms regulated by TMX2 and the consequences of its deficiency in a fly model. We identify TMX2 as an intracellular membrane protein that acts as a protective response to oxidative stress on MAMs. We propose that TMX2 forms a redox web that captures additional proteins involved in controlling oxidative stress, as well as multiple target proteins, thus mitigating oxidative damage and excessive activation of cellular metabolism. With the present proposal, we will uncover the molecular mechanisms underlying TMX2 function and provide insights into the shared causes and consequences of disrupted MAMs in genetic diseases.