Identification of cellular functions of cardiolipin as physiological modifiers of barth syndrome

IDENTIFICATION OF CELLULAR FUNCTIONS OF CARDIOLIPIN ASPHYSIOLOGICAL MODIFIERS OF BARTH SYNDROMEbyAMIT S. JOSHIDecember 2012 Advisor:Dr. Miriam L. GreenbergMajor:Biological SciencesDegree:Doctor of PhilosophyCardiolipin (CL) is an anionic phospholipid synthesized in themitochondrial inner membrane. Perturbation of CL metabolism leads to Barthsyndrome (BTHS), a life threatening genetic disorder. I utilized genetic,biochemical and cell biological approaches in yeast to elucidate the cellularfunctions of CL. Understanding the functions of CL is expected to shed lighton the pathology and possible treatments for BTHS.BTHS is caused by mutations in TAZ1, which encodes a CLremodeling enzyme called tafazzin. BTHS patients exhibit a wide range ofclinical presentations, indicating that physiological modifiers influence theBTHS phenotype. A targeted synthetic lethality screen was performed toidentify physiological modifiers of CL deficiency. Using this approach,synthetic genetic interactions of CL mutants were identified with genesencoding mitochondrial outer membrane proteins, specifically in the TOM,MDM and SAM complexes, which are involved in mitochondrial protein import,suggesting that CL plays a role in this process. Consistent with this, we