Abstract 1048 The Origin Story: From mitochondrial fuel switching to cellular differentiation

Energy balance and nutrient availability play critical roles in dictating cellular responses, including quiescence, proliferation, and differentiation into mature cell types. As cells assess their environmental context, the need arises to reprogram their metabolic machinery to facilitate distinct cellular outcomes. Recently, key studies from my group and others provide evidence that metabolic changes are not merely the end product of the altered cell state, but rather the key early regulators of cell determination. Our recent published work demonstrated the role of de novo nucleotide biosynthesis in adipogenesis. Specifically, we found that inhibition of nucleotide biosynthesis downregulates the expression of peroxisome proliferator-activated receptor γ (PPARγ), a key transcriptional driver of adipogenesis. Our new work now shows that inhibition of nucleotide biosynthesis reprograms mitochondrial metabolism, switching fuel usage from glucose to fatty acids. Nucleotides are known regulators of several key enzymes in glucose oxidation. Consequently, in the presence of inhibitors of nucleotide biosynthesis, the cells become reliant to fatty acid oxidation. Significantly, blocking fatty acid oxidation in the presence of inhibitors of nucleotide biosynthesis restores PPARγ and adipogenesis. These studies have revealed a new connection between mitochondrial metabolites and transcriptional regulation that modulates cell differentiation. By delineating the previously unrecognized connection between nucleotide biosynthesis and mitochondrial metabolism, we offer a new mechanistic perspective on how fuel utilization controls cell differentiation. This study was funded by a P30 058404 DDRTC Pilot and Feasibility Award, DK020593 Vanderbilt Diabetes and Research Training Center, the Vanderbilt University Seeding Success grant and AHA Career Development Award.