Deciphering the crosstalk between methionine metabolism and methyltransferases in health and disease

PROJECT SUMMARY/ABSTRACT Methionine metabolism is a central regulator of protein synthesis, mitochondrial function, antioxidant defense, and other critical cellular processes. Tightly regulating methionine flux via the methionine metabolism pathway is essential for healthy cellular function. Not surprisingly, an imbalance in this fundamental metabolic pathway has been attributed to numerous diseases. Yet, the molecular link between alterations in methionine availability and dysregulation of downstream cellular processes remains obscure. Methionine and ATP are the sole precursors for the production of the methyl donor S-adenosylmethionine (SAM), the principal and rate- limiting methyl donor for methyltransferases (MTs), which catalyze a variety of methylation reactions via the transfer of methyl groups onto different substrates. Although reprogramming of methionine metabolism has been observed with different pathological conditions, it is not known which downstream MTs link methionine metabolism to the development of these pathological conditions and what mediates the specificity of this interaction, representing a significant knowledge gap. I hypothesize that the identification of specific MTs will reveal novel mechanisms by which methionine metabolism regulates essential cellular processes. The goal of our research is to mechanistically understand how alterations in methionine are transduced into biological effects. To accomplish this goal, my laboratory will build and sustain three research projects. Through a preliminary screen, we identified several MTs that promote resistance to starvation or oxidative stress similar to manipulations of the methionine metabolism pathway. I will test several models to determine which MTs function downstream to methionine metabolism and complete the screen of the remaining MTs (Project 1). Secondly, I will test whether the tissue-specific expression of selected MTs help explain the specificity of how global changes in methionine levels affect specific MTs using a novel tissue-specific methionine degradation system that we recently developed (Project 2). Finally, we will use an open-ended proteomics approach to identify prospective downstream targets of the identified MTs and test how these MTs affect functional responses to stress (Project 3). These platforms interdigitate but also work independently, noting that we have already identified several MTs that promote resistance to different stresses, so Projects 2 and 3 can be performed independently of Project 1. We will employ innovative approaches by combining novel genetic tools that allow us to manipulate methionine levels within specific tissues and using a state-of- the-art approach to quantify methionine fate in vivo. The proposed research is significant because it will uncover how a central metabolic pathway (methionine) controls many basic cellular processes. This basic research is likely to further identify “druggable” targets relevant to multiple human pathologies associated with reprogrammed methionine metabolism including cancer, obesity, neurodegeneration, and aging.