Mechano‐energetic aspects of Barth syndrome

Abstract

Energy‐demanding organs like the heart are strongly dependent on oxidative phosphorylation in mitochondria. Oxidative phosphorylation is governed by the respiratory chain located in the inner mitochondrial membrane. The inner mitochondrial membrane is the only cellular membrane with significant amounts of the phospholipid cardiolipin, and cardiolipin was found to directly interact with a number of essential protein complexes, including respiratory chain complexes I to V. An inherited defect in the biogenesis of cardiolipin causes Barth syndrome, which is associated with cardiomyopathy, skeletal myopathy, neutropenia and growth retardation. Energy conversion is dependent on reducing equivalents, which are replenished by oxidative metabolism in the Krebs cycle. Cardiolipin deficiency in Barth syndrome also affects Krebs cycle activity, metabolite transport and mitochondrial morphology. During excitation‐contraction coupling, calcium (Ca2+) released from the sarcoplasmic reticulum drives sarcomeric contraction. At the same time, Ca2+ influx into mitochondria drives the activation of Krebs cycle dehydrogenases and the regeneration of reducing equivalents. Reducing equivalents are essential not only for energy conversion, but also for maintaining a redox buffer, which is required to detoxify reactive oxygen species (ROS). Defects in CL may also affect Ca2+ uptake into mitochondria and thereby hamper energy supply and demand matching, but also detoxification of ROS. Here, we review the impact of cardiolipin deficiency on mitochondrial function in Barth syndrome and discuss potential therapeutic strategies.

Stimulating myocardial pyruvate dehydrogenase activity fails to alleviate cardiac abnormalities in a mouse model of human Barth syndrome

“…This raises the important question as to why stimulating myocardial PDH activity would fail to yield benefit in TazKD mice, considering numerous other cardiac pathologies are corrected by such a metabolic strategy? We posit that the persistent destabilization of ETC supercomplexes and reduced ETC complex activity coupled with consequent elevations of mitochondrial reactive oxygen species and oxidative stress (10,11,(30)(31)(32), likely supersede intermediary metabolism defects present in BTHS. This may explain the failure of DCA treatment to attenuate the LV hypertrophic remodeling in TazKD mice despite an improvement of myocardial glucose oxidation.…”

Myocardial disturbances of intermediary metabolism in Barth syndrome

“…Notably, TAFAZZIN deficiency is associated with an impairment of mitochondrial respiratory capacity and ATP production, which to date, has largely been attributed to destabilization of the IMM electron transport chain (ETC) ( 18 ). Normal production of ATP in healthy mitochondria involves the oxidation of fatty acids, glucose, ketones, and amino acids to produce acetyl-CoA, which enters the Krebs cycle resulting in the generation of reducing equivalents (i.e., NADH and FADH 2 ) by its 4 dehydrogenase enzymes.…”

Barth syndrome and the many fascinating aspects of cardiolipin

“…Key features of each of the different model systems ranging from yeast to fruit fly, zebrafish, mice, and induced pluripotent stem cells, and their relevance to Barth syndrome are discussed. The next paper in line by Dudek and Maack 10 deals with the mechano‐energetic aspects of Barth syndrome induced by the impairment in cardiolipin synthesis and remodeling. Special attention is paid to calcium which plays a central role during excitation‐contraction with calcium released from the sarcoplasmic reticulum driving sarcomere contraction.…”

“…Special attention is paid to calcium which plays a central role during excitation‐contraction with calcium released from the sarcoplasmic reticulum driving sarcomere contraction. Mitochondria are key players in calcium homeostasis as mediated by the mitochondrial calcium uniporter (MCU) complex made up of several proteins and it has been shown that cardiolipin interacts with several of the regulatory subunits of the MCU‐complex including MICU1 and MICU2 with important ramifications for Barth syndrome 10 . The subsequent contribution by Bozelli and Epand 11 focuses on the consequences of the defect in cardiolipin metabolism observed in Barth syndrome on other lipids, notably plasmalogens which constitute a special class of lipid species characterized by the presence of an ether/vinyl‐ether rather than an ester bond at the sn ‐1 position of the glycerol backbone.…”

“…Mitochondria are key players in calcium homeostasis as mediated by the mitochondrial calcium uniporter (MCU) complex made up of several proteins and it has been shown that cardiolipin interacts with several of the regulatory subunits of the MCU-complex including MICU1 and MICU2 with important ramifications for Barth syndrome. 10 The subsequent contribution by Bozelli and Epand 11 focuses on the consequences of the defect in cardiolipin metabolism observed in Barth syndrome on other lipids, notably plasmalogens which constitute a special class of lipid species characterized by the presence of an ether/ vinyl-ether rather than an ester bond at the sn-1 position of the glycerol backbone. The authors show that plasmalogen levels-and to some extent also the cardiolipin levels-could be restored in cells from patients with Barth syndrome by supplementation of alkylglycerol, an ether lipid precursor, to the cell medium.…”