Deletion of the cardiolipin-specific phospholipase Cld1 rescues growth and life span defects in the tafazzin mutant: implications for Barth syndrome.

Abstract

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.

• Authors: Cunqi Ye, Wenjia Lou, Yiran Li, Iliana A Chatzispyrou, Maik Hüttemann, Icksoo Lee, Riekelt H Houtkooper, Frédéric M Vaz, Shuliang Chen, Miriam L Greenberg
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 289 Issue 6 Pg. 3114-25 (Feb 07 2014) ISSN: 1083-351X [Electronic] United States
• PMID: 24318983 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cardiolipins
• DNA, Fungal
• DNA, Mitochondrial
• Saccharomyces cerevisiae Proteins
• 1-Acylglycerophosphocholine O-Acyltransferase
• CLD1 protein, S cerevisiae
• Phospholipases

Topics

• 1-Acylglycerophosphocholine O-Acyltransferase (genetics, metabolism)
• Barth Syndrome
• Cardiolipins (genetics, metabolism)
• DNA, Fungal (genetics, metabolism)
• DNA, Mitochondrial (genetics, metabolism)
• Energy Metabolism (physiology)
• Gene Deletion
• Humans
• Mitochondria (genetics, metabolism)
• Oxygen Consumption (physiology)
• Phospholipases (genetics, metabolism)
• Saccharomyces cerevisiae (enzymology, genetics)
• Saccharomyces cerevisiae Proteins (genetics, metabolism)