TY - JOUR
T1 - Tafazzin deficiency impairs CoA-dependent oxidative metabolism in cardiac mitochondria
AU - Le, Catherine H.
AU - Benage, Lindsay G.
AU - Specht, Kalyn S.
AU - Li Puma, Lance C.
AU - Mulligan, Christopher M.
AU - Heuberger, Adam L.
AU - Prenni, Jessica E.
AU - Claypool, Steven M.
AU - Chatfield, Kathryn C.
AU - Sparagna, Genevieve C.
AU - Chicco, Adam J.
N1 - Funding Information:
Funding and additional information—This work was supported by grants from the Barth Syndrome Foundation and a Scientist Development Grant from the American Heart Association (to A. J. C.).
Funding Information:
We thank Carolyn Broccardo (Colorado State University) for assistance with the proteomic analyses, Cheyanne Izon and Philip Zilhaver (Colorado State University) for assistance with the immunoblotting, Victoria Harcy (Colorado State University) for assistance with maintenance of the TazKD mouse colony, and Michael J. Bennett (Children's Hospital of Philadelphia) for collaboration and technical assistance with optimizing the acyl-CoA analyses. Funding and additional information-This work was supported by grants from the Barth Syndrome Foundation and a Scientist Development Grant from the American Heart Association (to A. J. C.).
Publisher Copyright:
© 2020 Le et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2020/8/28
Y1 - 2020/8/28
N2 - Barth syndrome is a mitochondrial myopathy resulting from mutations in the tafazzin (TAZ) gene encoding a phospholipid transacylase required for cardiolipin remodeling. Cardiolipin is a 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 Barth syndrome 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 up-regulation 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.
AB - Barth syndrome is a mitochondrial myopathy resulting from mutations in the tafazzin (TAZ) gene encoding a phospholipid transacylase required for cardiolipin remodeling. Cardiolipin is a 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 Barth syndrome 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 up-regulation 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.
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U2 - 10.1074/jbc.ra119.011229
DO - 10.1074/jbc.ra119.011229
M3 - Article
C2 - 32665401
AN - SCOPUS:85090028247
VL - 295
SP - 12485
EP - 12497
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 35
ER -