Steven Michael Claypool, Ph.D.

The Claypool lab focuses on defining how lipids and membrane proteins interact to establish and maintain normal mitochondrial function and how derangements in this complex relationship result in pathophysiology.

Two nonbilayer phospholipids, cardiolipin and phosphatidylethanolamine are synthesized in mitochondria. Interestingly, in the yeast Saccharomyces cerevisiae, the cardiolipin and mitochondrial phosphatidylethanolamine biosynthetic pathways are synthetically lethal. Whereas phosphatidylethanolamine is normally associated with every membrane in the endomembrane system, cardiolipin is only found in the mitochondrion. Newly synthesized cardiolipin undergoes an acyl chain remodeling process. One pathway of cardiolipin remodeling is executed by the cardiolipin transacylase, tafazzin, the mutant gene product associated with the X–linked disease Barth syndrome. The Claypool lab has demonstrated that yeast lacking tafazzin recapitulates all phospholipid abnormalities observed in human patients and many mitochondrial defects. Further, they developed a yeast model of Barth syndrome in which each pathogenic missense mutation identified in the Barth syndrome patient population is individually modeled in the yeast tafazzin ortholog, allowing a molecular determination of the loss-of-function mechanism of each disease allele.

Another major project in the Claypool lab examines the mitochondrial ADP/ATP carrier required for oxidative phosphorylation. Surprisingly, the lab has recently demonstrated that AAC2 physically associates with the respiratory supercomplex and possibly other mitochondrial carriers. Further, all of these completely novel interactions require cardiolipin. How these novel interactions help establish normal mitochondrial function, the biochemical details of these associations, and whether disturbances in these assemblies can contribute to mitochondrial dysfunction are at present unaddressed and extremely important questions.