Elucidating the role of cardiolipin in mitochondrial and cellular functions



Cardiolipin (CL), the signature phospholipid of mitochondria, is crucial not only for mitochondrial function but also for a plethora of cellular processes that are not associated with mitochondrial bioenergetics. The de novo synthesis of CL is followed by a remodeling cycle of deacylation (removal of a fatty acid) followed by reacylation. Specific fatty acyl composition is acquired during this process, and remodeled CL contains predominantly unsaturated fatty acids.  The importance of CL remodeling is underscored by the life-threatening genetic disorder Barth syndrome (BTHS), caused by mutations in tafazzin, the enzyme that reacylates CL.



CL-deficient mutants have been instrumental in elucidating the functions of this unique lipid.  We identified the first CL mutant (crd1Δ), which cannot synthesize CL, and we developed the yeast model for BTHS, the taz1Δ mutant, which lacks tafazzin. Utilizing these mutants, we have determined that CL is required for optimal mitochondrial bioenergetics and energy metabolism; mitochondrial protein import; mitochondrial fusion; function of the vacuole, the vacuolar ATPase, and vacuolar autophagy; iron-sulfur biogenesis; and MAPK signaling. Furthermore we have shown that genetically blocking the CL deacylation step rescues the defective phenotypes of the tafazzin mutant.



Our current studies are focused on elucidating the mechanisms whereby CL controls these diverse cellular activities.  Our approach is to utilize the power of the yeast model to develop hypotheses that can be tested in appropriate mammalian systems. Specifically, our research addresses the following questions:



1. How does CL deficiency perturb cellular energy metabolism?


2. What is the mechanism linking CL to iron-sulfur biogenesis?


3. What is the role of CL in MAPK signaling, vacuolar function, and autophagy?


4. What is the function of CL remodeling?


5. What defects associated with CL deficiency lead to the pathologies in BTHS and other CL-associated disorders, including diabetic cardiomyopathy, heart failure, and ischemia/reperfusion injury?

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