Metabolite Toxicity as a Driver
of Aging and Disease
Amino acids are a basic building block of life, serving as precursors for protein biosynthesis and other cellular metabolites, and as metabolic fuel for cellular energy production. However, like many metabolites, elevated levels of amino acids can become toxic, and function as drivers of aging, and both common (diabetes) and rare (inborn errors of amino acid metabolism) metabolic disorders. It has become clear in recent years that cells have evolved mechanisms to spatially compartmentalize amino acids within organelles, and recent work from our lab suggests that a breakdown in the function of the lysosome—a major amino acid sequestering organelle—impacts cellular health by causing localized amino acid toxicity. How elevated intracellular levels of amino acids are toxic for cells, and what amino acids are problematic is currently unknown. We are pursuing projects in both yeast and mammals to dissect mechanisms of amino acid toxicity, and to elucidate how elevated levels of amino acids underlie the development of a host of metabolic disorders, including diabetes and rare genetic diseases associated with faulty amino acid metabolism.