Loss of mitochondrial quality control protein Yme1 is deleterious to the viability of yeast lacking tafazzin.

Abstract

The Saccharomyces cerevisiae TAZ1 gene is an orthologue of human TAZ; both encode the protein tafazzin. Tafazzin is a transacylase that transfers acyl chains with unsaturated fatty acids from other phospholipids to monolysocardiolipin (MLCL) to generate cardiolipin (CL) with a prevalence of unsaturated fatty acids. Transacylase activity is evolutionarily conserved between yeast and humans, as TAZ1 deficiency in yeast can be compensated for by the expression of human TAZ. Mutations in human TAZ cause Barth Syndrome (BTHS), a fatal infant disease biochemically characterized by reduced CL mass, increased MLCL levels and mitochondrial dysfunction. Although a plethora of symptoms are manifested, children with BTHS primarily suffer from cardiomyopathy and neutropenia. How an inability of tafazzin to function results in Barth syndrome pathology is not clear. To uncover cellular processes that require tafazzin to maintain cell health, I performed a Synthetic Genetic Array (SGA) analysis using taz1∆ yeast cells to identify genes whose deletion aggravated their fitness. The genome-wide screen identified that the mitochondrial quality-control protein Yme1 was crucial for yeast cell growth in the absence of tafazzin function. I then explored mechanisms that lead to the decrease in cell fitness in yeast lacking both tafazzin and Yme1, and found severe mitochondrial ultrastructural defects, defective mitophagy and ineffective superoxide scavenging. Mitophagy is a quality-control process cells use to rid themselves of damaged mitochondria. I show that these are not caused by gross changes in mitochondrial phospholipid levels, increased superoxide generation, or abnormal vacuolar function. I was able to identify an important role for tafazzin in mitochondrial dynamics. The SGA screen also uncovered several other cellular processes that require tafazzin that can be explored by future researchers interested in CL metabolism, mitochondrial function, or Barth syndrome.