Yeast as a system for modeling mitochondrial disease mechanisms and discovering therapies

Abstract

Mitochondrial diseases are severe and largely untreatable. Owing to the many essential processes carried out by mitochondria and the complex cellular systems that support these processes, these diseases are diverse, pleiotropic, and challenging to study. Much of our current understanding of mitochondrial function and dysfunction comes from studies in the baker's yeast Saccharomyces cerevisiae. Because of its good fermenting capacity, S. cerevisiae can survive mutations that inactivate oxidative phosphorylation, has the ability to tolerate the complete loss of mitochondrial DNA (a property referred to as ‘petite-positivity’), and is amenable to mitochondrial and nuclear genome manipulation. These attributes make it an excellent model system for studying and resolving the molecular basis of numerous mitochondrial diseases. Here, we review the invaluable insights this model organism has yielded about diseases caused by mitochondrial dysfunction, which ranges from primary defects in oxidative phosphorylation to metabolic disorders, as well as dysfunctions in maintaining the genome or in the dynamics of mitochondria. Owing to the high level of functional conservation between yeast and human mitochondrial genes, several yeast species have been instrumental in revealing the molecular mechanisms of pathogenic human mitochondrial gene mutations. Importantly, such insights have pointed to potential therapeutic targets, as have genetic and chemical screens using yeast.

Drug screening using model systems: some basics

“…My goal in this piece is not to review how to screen drugs using model systems – there are plenty of excellent reviews on this subject already (Phillips and Westerfield, 2014; Gopinathan et al, 2015; Asnani and Peterson, 2014; Veinotte et al, 2014; Lasserre et al, 2015; Simon and Bedalov, 2004; Kaletta and Hengartner, 2006; Yadav et al, 2016). My goal is to share some of the knowledge my group has gained over the years on how to think about drug screening.…”

Overexpression of mitochondrial oxodicarboxylate carrier (ODC1) preserves oxidative phosphorylation in a yeast model of the Barth syndrome

“…Much of what we know about BTHS comes from studies in the yeast Saccharomyces cerevisiae , which is a convenient system for modelling mitochondrial disease mechanisms (Baile and Claypool, 2013; Lasserre et al, 2015). Studies in this yeast have helped to define how CL is synthesized and remodeled to maintain a homogenous and highly unsaturated acyl-chain composition, and how mitochondria are influenced by defects in these processes (Claypool, 2009; Joshi et al, 2009; Baile et al, 2014b; Mileykovskaya and Dowhan, 2014).…”

“…The common respiratory growth defect observed in yeast models of mitochondrial disease provides a simple read-out to enable large-scale screens for genetic suppressors able to rescue mitochondrial dysfunction (Baile and Claypool, 2013; Lasserre et al, 2015). Even when mitochondrial dysfunction is severe enough to abolish respiratory growth, yeast offers the unique advantage that such mutants can be kept alive and propagated on fermentable substrates for the use in suppressor screens.…”

Knockdown of Sucla2 decreases the viability of mouse spermatocytes by inducing apoptosis through injury of the mitochondrial function of cells

“…Mitochondria are complex organelles that not only participate in ATP synthesis and ROS production, but also play important roles in proliferation, differentiation, and apoptosis of germ cells [17,18]. Mitochondrial function depends not only on mitochondrial molecules encoded by nuclear DNA (nDNA), but also depends on molecules encoded by mitochondria DNA (mtDNA) [19,20]. The literature shows that many kinds of abnormal expression of mitochondrial proteins are associated with mitochondrial dysfunction, resulting in mitochondrial diseases such as neurodegeneration, cancer, infertility, and ageing [21][22][23].…”