Determine the role of a monocarboxylate transporter in metabolism and intestinal motility

About This Grant

PROJECT SUMMARY Monocarboxylate transporters (MCTs) mediate the transport of key metabolic intermediates, such as lactate, urate, and pyruvate, across cellular membranes. Despite their importance in metabolic homeostasis and their implication in a range of diseases—including cancer, cardiovascular disease, and neurodegeneration—the MCT family remains poorly understood. Novel approaches are needed to study the role of MCTs in physiology and disease. MCTs are highly conserved in the nematode Caenorhabditis elegans. C. elegans is a highly tractable genetic model, and its defined anatomy, simple diet, and optical transparency offers several advantages for studying conserved molecular and physiological processes. Through a genetic screen for mutants with defecation defects, I found that a point mutation in slcf-1 causes a shortened defecation cycle. slcf-1 is expressed in the intestine and regulates intestinal calcium waves (ICWs) that drive the defecation motor program (DMP). These findings implicate a novel role for MCTs, metabolism and Ca²⁺ homeostasis. slcf-1 shares homology with MCT9, which has been implicated in hyperuricemia and can contribute to cardiovascular disease, gout, and renal cell carcinoma. The overarching goal of this project is to define the role of slcf-1 in intestinal Ca2+ dynamics and metabolism. In Aim 1, I will analyze how mutations in slcf-1 affect Ca²⁺ waves. I will quantify ICW properties, such as intervals and rise and fall times, perform tissue-specific rescue, and examine SLCF-1::GFP localization. In Aim 2, I will determine SLCF-1 substrates and how SLCF-1 is dynamically regulated using HEK293T transport assays and mutant slcf-1 promotor constructs. Finally, in Aim 3, I will investigate the metabolic consequences of slcf-1 loss, assessing mitochondrial morphology, activity, and stress, alongside broader metabolic pathway alterations. These studies will provide greater insight into how conserved monocarboxylate transporters connect metabolism, calcium signaling, and intestinal motility, and promote a broader understanding of MCTs’ role in human health and disease.