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Multiple human diseases or conditions are associated with a perturbed cellular reduction-oxidation (redox) environment. Such pathologies include disorders caused by defects in the mitochondrial electron transport chain (ETC), neurodegeneration, cancer, cardiovascular disease and aging itself. However, at present, for most of these conditions it is not known which particular metabolic or signaling pathway, and which cellular compartment, is a major contributor to the redox imbalance. In order to address this critical challenge, it is necessary to have tools with which key contributors to the cellular redox environment can be safely and directly modulated in a compartment specific manner. Evolutionary adaptations in some bacteria, lower eukaryotes or plants offer attractive possibilities for developing such tools. These organisms sometimes use very different strategies for maintaining their optimal redox environment compared to mammalian cells.

The long-term goal of the Cracan lab is to apply quantitative metabolomics, structural enzymology and protein engineering methods to study cellular metabolism and bioenergetics in normal physiology and disease. Specifically, we will (1) explore evolutionary adaptations in organisms lacking a conventional ETC; (2) develop genetically-encoded tools for redox signaling research; and (3) elucidate how cellular metabolism is contributing to cancer and aging-associated neurodegenerative diseases. For example, we are interested in how reactive oxygen species (ROS)-generating and antioxidant systems differ between normal and cancer cells, as these differences may ultimately be exploited for therapeutic intervention. In addition, if the organ pathologies associated with mitochondrial disease or other conditions stem from redox imbalance, then our tools can be used as long-awaited therapeutics for these devastating conditions.

Valentin Cracan, PhD

@VFCracan