Cardiolipin (CL) that is synthesized de novo is deacylated to 
monolysocardiolipin (MLCL), which is reacylated by tafazzin. Remodeled CL 
contains mostly unsaturated fatty acids. In eukaryotes, loss of tafazzin leads 
to growth and respiration defects, and in humans, this results in the 
life-threatening disorder Barth syndrome. Tafazzin deficiency causes a decrease 
in the CL/MLCL ratio and decreased unsaturated CL species. Which of these 
biochemical outcomes contributes to the physiological defects is not known. 
Yeast cells have a single CL-specific phospholipase, Cld1, that can be exploited 
to distinguish between these outcomes. The cld1Δ mutant has decreased 
unsaturated CL, but the CL/MLCL ratio is similar to that of wild type cells. We 
show that cld1Δ rescues growth, life span, and respiratory defects of the taz1Δ 
mutant. This suggests that defective growth and respiration in 
tafazzin-deficient cells are caused by the decreased CL/MLCL ratio and not by a 
deficiency in unsaturated CL. CLD1 expression is increased during respiratory 
growth and regulated by the heme activator protein transcriptional activation 
complex. Overexpression of CLD1 leads to decreased mitochondrial respiration and 
growth and instability of mitochondrial DNA. However, ATP concentrations are 
maintained by increasing glycolysis. We conclude that transcriptional regulation 
of Cld1-mediated deacylation of CL influences energy metabolism by modulating 
the relative contribution of glycolysis and respiration.