Miriam L. Greenberg, PhD
Professor, Department of Biological Sciences, Wayne State University

“Elucidating the link between cardiolipin, mitochondrial metabolism, and myogenesis”

Abstract

Cardiolipin (CL), the most structurally unique phospholipid in the mitochondrial membrane, interacts with a myriad of proteins required for optimal mitochondrial function. The transacylase tafazzin (Taz) catalyzes the incorporation of unsaturated acyl chains into CL in the functionally enigmatic process of CL remodeling. Perturbation of CL remodeling due to mutation of Taz leads to the severe disorder, Barth syndrome (BTHS), underscoring the importance of remodeling. Cardiomyopathy and metabolic dysregulation are key pathological components of BTHS. The mechanistic connection between remodeling of CL and regulation of cellular metabolism is an unresolved mystery of basic metabolic regulation and BTHS pathology.

We have identified a crucial link between CL and cellular metabolism. Taz-deficient cells exhibit abnormal levels of tricarboxylic acid (TCA) cycle intermediates. Importantly, these cells exhibit decreased activity of pyruvate dehydrogenase (PDH), the gatekeeper enzyme for TCA cycle carbon influx. Decreased PDH activity can be rescued in mitochondria by supplementing with tetralinoleoyl-CL (TLCL), the primary product of CL remodeling in heart and skeletal muscle. These findings demonstrate for the first time that CL homeostasis plays a pivotal regulatory role in metabolism by maintaining activity of the central metabolic enzyme, PDH.