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.
Lab Website: Steven Claypool Lab
Baile MG, Whited K, Claypool SM. “Deacylation on the matrix side of the mitochondrial inner membrane regulates cardiolipin remodeling.” Mol Biol Cell. 2013 Jun;24(12):2008-20
Baile MG and Claypool SM. “The power of yeast to model diseases of the powerhouse of the cell.” Front Biosci. 2013 Jan 1;18:241-78.
Whited K, Baile MG, Currier P, Claypool SM. “Seven functional classes of Barth syndrome mutation.” Hum Mol Genet. 2013 Feb 1; 22(3): 483-492.
Claypool SM and Koehler CM. “The Complexity of Cardiolipin in Health and Disease.” Trends Biochem Sci. 2012 Jan;37(1): 32-41.
Tamura Y, Onguka O, Hobbs AE, Jensen RE, Iijima M, Claypool SM, Sesaki H. “Role for two conserved intermembrane space proteins, Ups1p and Up2p, in intra-mitochondrial phospholipid trafficking.” J Biol Chem. 2012 May 4;287(19):15205-18
Tamura Y, Onguka O, Itoh K, Endo T, Iijima M, Claypool SM, Sesaki H. “Phosphatidylethanolamine biosynthesis in mitochondria: phosphatidylserine (PS) trafficking is independent of a PS decarboxylase and intermembrane space proteins, Ups1p and Ups2p.” J Biol Chem. 2012 Dec 21;287(52):43961-71
Claypool SM, Whited K, Srijumnong S, Han X, Koehler CM. “Barth syndrome mutations that cause tafazzin complex lability.” J Cell Biol. 2011 Feb 7;192(3):447-62