J Biol Chem. 2020 Jul 14. pii: jbc.RA119.011229. [Epub ahead of print]
Catherine H Le,
Lindsay G Benage,
Kalyn S Specht,
Lance C Li Puma,
Christopher M Mulligan,
Adam L Heuberger,
Jessica E Prenni,
Steven M Claypool,
Kathryn C Chatfield,
Genevieve C Sparagna,
Adam J Chicco.
Barth syndrome (BTHS) is a mitochondrial myopathy resulting from mutations in the tafazzin (TAZ) gene encoding a phospholipid transacylase required for cardiolipin remodeling. Cardiolipin is phospholipid of the inner mitochondrial membrane essential for the function of numerous mitochondrial proteins and processes. However, it is unclear how tafazzin deficiency impacts cardiac mitochondrial metabolism. To address this question while avoiding confounding effects of cardiomyopathy on mitochondrial phenotype, we utilized Taz-shRNA "knockdown" (TazKD ) mice, which exhibit defective cardiolipin remodeling and respiratory supercomplex instability characteristic of human BTHS, but normal cardiac function into adulthood. Consistent with previous reports from other models, mitochondrial H2O2 emission and oxidative damage were greater in TazKD than in wild-type (WT) hearts, but there were no differences in oxidative phosphorylation coupling efficiency or membrane potential. Fatty acid and pyruvate oxidation capacities were 40-60% lower in TazKD mitochondria, but an upregulation of glutamate oxidation supported respiration rates approximating those with pyruvate and palmitoylcarnitine in WT. Deficiencies in mitochondrial CoA and shifts in the cardiac acyl-CoA profile paralleled changes in fatty acid oxidation enzymes and acyl-CoA thioesterases suggesting limitations of CoA availability or "trapping" in TazKD mitochondrial metabolism. Incubation of TazKD mitochondria with exogenous CoA partially rescued pyruvate and palmitoylcarnitine oxidation capacities, implicating dysregulation of CoA-dependent intermediary metabolism rather than respiratory chain defects in the bioenergetic impacts of tafazzin-deficiency. These findings support links among cardiolipin abnormalities, respiratory supercomplex instability and mitochondrial oxidant production, and shed new light on the distinct metabolic consequences of tafazzin-deficiency in the mammalian heart.
Keywords: Barth Syndrome (BTHS); X-linked mitochondrial disorder; bioenergetics; cardiolipin; cardioskeletal myopathy; lipid metabolism; mitochondrial disease; mitochondrial metabolism; phospholipid transacylase; tafazzin (TAZ)