Studying Lipid-Related Pathophysiology Using the Yeast Model

Abstract

Saccharomyces cerevisiae, commonly known as baker’s yeast, is one of the most comprehensively studied model organisms in science. Yeast has been used to study a wide variety of human diseases, and the yeast model system has proved to be an especially amenable tool for the study of lipids and lipid-related pathophysiologies, a topic that has gained considerable attention in recent years. This review focuses on how yeast has contributed to our understanding of the mitochondrial phospholipid cardiolipin (CL) and its role in Barth syndrome (BTHS), a genetic disorder characterized by partial or complete loss of function of the CL remodeling enzyme tafazzin. Defective tafazzin causes perturbation of CL metabolism, resulting in many downstream cellular consequences and clinical pathologies that are discussed herein. The influence of yeast research in the lipid-related pathophysiologies of Alzheimer’s and Parkinson’s diseases is also summarized.

A new technology for isolating organellar membranes provides fingerprints of lipid bilayer stress

“…Yet, the contribution of lipid bilayer stress to health and disease remains understudied (Hotamisligil, 2010). Yeast is an ideal model organism to decipher fundamental (patho)mechanisms of the lipid metabolic network, the secretory pathway, membrane traffic, and membrane homeostasis (Kurat et al , 2006; Henry et al , 2012; Ralph-Epps et al , 2021). Recent advances in quantitative lipidomics (Ejsing et al , 2009) have provided deep insight into the flexibility and adaptation of the cellular lipidome to various metabolic and physical stimuli in both yeast and mammals (Klose et al , 2012; Casanovas et al , 2015; Levental et al , 2020; Surma et al , 2021).…”

Cytochrome c Interaction with Cardiolipin Plays a Key Role in Cell Apoptosis: Implications for Human Diseases

“…The over 100 CL molecular species present in the brain are characterized by an increased presence of arachidonic acid and docosahexaenoic acids that are known as signaling fatty acids. The lower symmetrical profile [70] is likely responsible for the reduced mitochondrial bio-energetic efficiency in brain tissue. Interestingly, in some tumors, abnormalities in the CL content or composition were found (i.e., a great amount of immature molecular species and a scarcity of mature molecular species due to major defects in CL synthesis and remodeling) [69][70][71].…”

“…The lower symmetrical profile [70] is likely responsible for the reduced mitochondrial bio-energetic efficiency in brain tissue. Interestingly, in some tumors, abnormalities in the CL content or composition were found (i.e., a great amount of immature molecular species and a scarcity of mature molecular species due to major defects in CL synthesis and remodeling) [69][70][71].…”

“…Indeed, several steps of modifications of phosphatidic acid (PA) within the mitochondrion, where CL is uniquely utilized, characterize the CL biosynthetic pathway. From yeast to upper eukaryotes, CL biosynthesis in mitochondria are typical highly conserved and well-characterized steps [69][70][71][72][73]. The conversion of mitochondrial phosphatidic acid (PA) into cytidine diphosphodiacylglycerol (CDP-DAG) by the mitochondrial CDP-DAG synthase (CDS) is the first reaction of CL biosynthesis.…”

“…PGP phosphatase codified by PTPMT in mammals catalyzes the subsequent dephosphorylation of PGP to phosphatidylglycerol (PG). Next, CL synthase (CLS) catalyzes the final reaction of "de novo" CL synthesis by adding a phosphatidyl group from CDP-DAG to PG [69][70][71][72][73].…”