Myocardial disturbances of intermediary metabolism in Barth syndrome

Abstract

Barth Syndrome (BTHS) is a rare X-linked mitochondrial disorder due to mutations in the gene TAFAZZIN, which leads to immature cardiolipin (CL) remodeling and is characterized by the development of cardiomyopathy. The immature CL remodeling in BTHS results in electron transport chain respiratory defects and destabilization of supercomplexes, thereby impairing ATP production. Thus, BTHS-related cardiomyopathy appears to share metabolic characteristics of the failing heart being an “engine out of fuel.” As CL associates with numerous mitochondrial enzymes involved in ATP production, BTHS is also characterized by several defects in intermediary energy metabolism. Herein we will describe the primary disturbances in intermediary energy metabolism relating to the heart's major fuel sources, fatty acids, carbohydrates, ketones, and amino acids. In addition, we will interrogate whether these disturbances represent potential metabolic targets for alleviating BTHS-related cardiomyopathy.

Reduction in activity and abundance of mitochondrial electron transport chain supercomplexes in pulmonary hypertension-induced right ventricular dysfunction

“…Studies of mSC in long term heart failure studies are much more limited. Genetic models of Barth Syndrome involving Tafazzin KO or KD have demonstrated there are decreases in mSC (due to cardiolipin disturbances) that associate with development of cardiomyopathy [9, 42]. However, there are gross mitochondrial structural alterations with Tafazzin KO/KD confounding clear interpretation regarding the importance of mSC assembly.…”

Tafazzin regulates neutrophil maturation and inflammatory response

“…Tafazzin is essential for remodeling and maturation of cardiolipin (CL), a major phospholipid of the mitochondrial inner membrane, which has a crucial role in maintaining mitochondrial structure and function [2, 5]. TAFAZZIN mutations lead to an accumulation of an intermediate CL species, monolysocardiolipin (MLCL), impairing mitochondrial metabolism and contributing to defects in cardiomyocytes and skeletal muscle, which have abundant mitochondria and are dependent on efficient oxidative respiration [6]. Apart from regulating ATP generation, CL has been implicated in signaling [7, 8], control of apoptosis [8, 9], generation of mitochondrial reactive oxygen species (ROS) [9], and regulation of calcium homeostasis [10].…”