Faculty & Research
|School of Medicine Address||725 N Wolfe St|
Baltimore MD 21205
|Link to Lab Homepage|
Research Topic: Mitochondrial Phospholipid Metabolism in Health and Disease.
The research in the Claypool lab is broadly interested in defining how lipids and membrane proteins interact to establish and maintain normal mitochondrial function and how derangements in this complex relationship result in pathophysiology. The mitochondrion’s role in phospholipid metabolism is vastly underappreciated. 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. For this reason, cardiolipin is often called the signature phospholipid of the powerhouse of the cell. Cardiolipin is a dimeric lipid. 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 of the phospholipid abnormalities observed in human patients and many of the mitochondrial defects. Further, the Claypool lab developed a yeast model of Barth syndrome in which each of the pathogenic missense mutations 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 focuses on the mitochondrial ADP/ATP carrier which is required for oxidative phosphorylation. For the past 35 years, the major ADP/ATP carrier in S. cerevisiae, AAC2, was thought to participate in oxidative phosphorylation as an individual, membrane-embedded unit. Surprisingly, we 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.
Baile MG, Sathappa M, Lu YW, Pryce E, Whited K, McCaffery JM, Han X, Alder NN, Claypool SM
. Unremodeled and remodeled cardiolipin are functionally indistinguishable in yeast. J Biol Chem. 2014 Jan 17;289(3):1768-78.PubMed Reference
Baile MG, Lu YW, Claypool SM
. The topology and regulation of cardiolipin biosynthesis and remodeling in yeast. Chem Phys Lipids. 2013 Nov 1. pii: S0009-3084(13)00136-9.PubMed Reference
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.PubMed Reference
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.PubMed Reference
Baile MG and Claypool SM
. The power of yeast to model diseases of the powerhouse of the cell. Front Biosci. 2013 Jan 1;18:241-78PubMed Reference
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 *Corresponding AuthorsPubMed Reference
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 *Corresponding AuthorPubMed Reference