Cardiolipin function in the yeast S. cerevisiae and the lessons learned for Barth syndrome

Abstract

Cardiolipin (CL) is the signature phospholipid (PL) of mitochondria and plays a pivotal role in mitochondrial and cellular function. Disruption of the CL remodeling gene tafazzin (TAZ) causes the severe genetic disorder Barth syndrome (BTHS). Our current understanding of the function of CL and the mechanism underlying the disease has greatly benefited from studies utilizing the powerful yeast model Saccharomyces cerevisiae. In this review, we discuss important findings on the function of CL and its remodeling from yeast studies and the implications of these findings for BTHS, highlighting the potential physiological modifiers that may contribute to the disparities in clinical presentation among BTHS patients.

Keywords: Barth syndrome; cardiolipin; mitochondrial disease; tafazzin; yeast.

Fig. 1.. Biosynthesis and remodeling of CL in yeast.

PA, phosphatidic acid; CDP-DAG, cytidine diphosphate diacylglycerol; PGP, phophatidylglycerolphosphate; PG, phosphatidylglycerol; CL, cardiolipin; MLCL, monolysocardiolipin; Tam41, mitochondrial phosphatidate cytidylyltransferase (CDP-DGA synthase); Pgs1, PGP synthase; Gep4, PGP phosphatase; Crd1, CL synthase; Cld1, CL-specific phospholipase; Taz1, acyltransferase.

Fig. 2.. Findings in yeast suggest potential physiological modifiers that contribute to the broad spectrum of phenotypes in BTHS patients.

BTHS patients exhibit a broad range of clinical abnormalities, suggesting the existence of physiological modifiers that affect the clinical presentations and treatment outcomes. Studies using yeast CL mutants, especially crd1Δ, taz1Δ, and cld1Δ, have provided insight into CL functions. We suggest that several functions of CL elucidated in studies with the yeast model may be potential physiological modifiers that contribute to the diverse clinical presentations among patients.