Cardiolipin (CL), the signature lipid of the mitochondrial membrane, is required for optimal mitochondrial function, as well as mitochondrial protein import, mitochondrial fusion, PKC and osmotic stress signaling pathways, aging, vacuole/lysosome function, and ceramide synthesis. CL is found in all mammalian tissues, but it is most abundant in the heart, where it comprises up to 20% of phospholipids. Perturbation of CL synthesis leads to the severe life- threatening genetic disorder known as Barth syndrome (BTHS), which is characterized by dilated cardiomyopathy and a high incidence of sudden death from arrhythmia. CL deficiency is also implicated in diabetic cardiomyopathy, heart failure, ischemia/reperfusion injury, and nonalcoholic fatty liver disease. Elucidating the mechanisms underlying the involvement of CL in cellular functions would provide insight into these disorders and identify potential new drug targets. The yeast model has been pivotal in elucidating the functions of CL, as it offers numerous advantages not currently available in other eukaryotic systems. It is the only eukaryote in which null mutants are available for every step in CL synthesis. Furthermore, a vast array of genetic, biochemical, and functional genomic analyses can more readily be applied in yeast than in other eukaryotic models. Conservation of function from yeast to humans for disease-associated genes as well as for complex cellular processes makes it likely that knowledge gleaned from yeast studies will be applicable to humans. We will utilize the yeast system as well as CL-deficient mammalian cells to test the novel hypothesis that CL deficiency leads to defective mitochondrial import of proteins required for iron-sulfur (Fe S) biogenesis, resulting in perturbation of the TCA cycle and metabolic deficiencies.
Aim 1 will define the mechanism that links CL deficiency to perturbation of Fe-S biogenesis and the TCA cycle in yeast.
Aim 2 will identify specific defects in Fe-S biogenesis and the TCA cycle that result from CL deficiency in mammalian cells. This knowledge will facilitate our understanding of highly conserved mechanisms that control mitochondrial metabolism, and will offer the possibility of new directions for the diagnosis and treatment of BTHS and other cardiomyopathies and disorders.
Cardiolipin is a critically important mitochondrial lipid that is found in all tissues and is most abundant in the heart. Cardiolipin deficiency leads to dilated cardiomyopathy and arrhythmia in the genetic disorder Barth syndrome, and is also implicated in diabetic cardiomyopathy, heart failure, ischemia/reperfusion injury, and nonalcoholic fatty live disease. The proposed study will identify specific metabolites that are limiting as a result of cardiolipin deficiency, and that may be candidates for new treatments for Barth syndrome and other cardiomyopathies.