Biochemistry of Human Paraganglioma

The Nucleic Acid Structure and Recognition Laboratory is interested in the peculiar genetics and biochemistry of paraganglioma (PGL), a human neuroendocrine tumor. A leading cause of this tumor involves flaws in the tricarboxylic acid (TCA) cycle of central metabolism. Inherited mutations in subunits of TCA cycle enzyme succinate dehydrogenase (SDH) predispose to PGL.

The Maher laboratory has developed and studied the first yeast model of SDH dysfunction. Ongoing research with this yeast model includes a high-throughput small molecule screen for agents selectively toxic to SDH mutant yeast, as well as screening for agents that reduce succinate toxicity. Such agents could give insight for human PGL therapeutics. The Maher laboratory was the first to suggest and then demonstrate that succinate accumulation in SDH-deficient cells can poison an entire class of dioxygenase enzymes, including histone demethylases important in epigenetic regulation.

The Maher lab was also the first to create and test a heterozygous succinate dehydrogenase complex iron sulfur subunit B (SDHB) gene disruption mouse model for PGL susceptibility. Leveraging the unique Mayo Clinic practice in PGL, the Maher lab collaborates to study tumor tissue arrays. The laboratory is using synthetic lethal genetic screens to understand potential vulnerabilities in SDH-deficient cells. Work continues to understand how other defects, such as protein hyperacylation, may contribute to epigenetic dysregulation in SDH-deficient cells. The laboratory is studying multiple new approaches for development of PGL models in mice.

Jim Maher, Ph.D., discusses paraganglioma and the Paradifference Foundation, which supports Mayo Clinic research through the generosity of the Gustavsson family and other benefactors.