Acetylation and succinylation contribute to maturational alterations in energy metabolism in the newborn heart.
Dramatic maturational changes in cardiac energy metabolism occur in the newborn period, with a shift from glycolysis to fatty acid oxidation. Acetylation and succinylation of lysyl residues are novel posttranslational modifications involved in the control of cardiac energy metabolism. We investigated the impact of changes in protein acetylation/succinylation on the maturational changes in energy metabolism of 1-, 7-, and 21-day-old rabbit hearts. Cardiac fatty acid β-oxidation rates increased in 21-day vs. 1- and 7-day-old hearts, whereas glycolysis and glucose oxidation rates decreased in 21-day-old hearts. The fatty acid oxidation enzymes, long-chain acyl-CoA dehydrogenase (LCAD) and β-hydroxyacyl-CoA dehydrogenase (β-HAD), were hyperacetylated with maturation, positively correlated with their activities and fatty acid β-oxidation rates. This alteration was associated with increased expression of the mitochondrial acetyltransferase, general control of amino acid synthesis 5 like 1 (GCN5L1), since silencing GCN5L1 mRNA in H9c2 cells significantly reduced acetylation and activity of LCAD and β-HAD. An increase in mitochondrial ATP production rates with maturation was associated with the decreased acetylation of peroxisome proliferator-activated receptor-γ coactivator-1α, a transcriptional regulator for mitochondrial biogenesis. In addition, hypoxia-inducible factor-1α, hexokinase, and phosphoglycerate mutase expression declined postbirth, whereas acetylation of these glycolytic enzymes increased. Phosphorylation rather than acetylation of pyruvate dehydrogenase (PDH) increased in 21-day-old hearts, accounting for the low glucose oxidation postbirth. A maturational increase was also observed in succinylation of PDH and LCAD. Collectively, our data are the first suggesting that acetylation and succinylation of the key metabolic enzymes in newborn hearts play a crucial role in cardiac energy metabolism with maturation.
Cardiovascular Translational Science Institute, University of Alberta, Edmonton, Alberta, Canada; and.
Arata
A
Fukushima
Cardiovascular Translational Science Institute, University of Alberta, Edmonton, Alberta, Canada; and Faculty of Pharmacy, Yarmouk University, Irbid, Jordan.
Osama Abo
OA
Alrob
Cardiovascular Translational Science Institute, University of Alberta, Edmonton, Alberta, Canada; and.
Liyan
L
Zhang
Cardiovascular Translational Science Institute, University of Alberta, Edmonton, Alberta, Canada; and.
Cory S
CS
Wagg
Cardiovascular Translational Science Institute, University of Alberta, Edmonton, Alberta, Canada; and.
Tariq
T
Altamimi
Cardiovascular Translational Science Institute, University of Alberta, Edmonton, Alberta, Canada; and.
Sonia
S
Rawat
Cardiovascular Translational Science Institute, University of Alberta, Edmonton, Alberta, Canada; and.
Ivan M
IM
Rebeyka
Cardiovascular Translational Science Institute, University of Alberta, Edmonton, Alberta, Canada; and.
Paul F
PF
Kantor
Cardiovascular Translational Science Institute, University of Alberta, Edmonton, Alberta, Canada; and gary.lopaschuk@ualberta.ca.
Gary D
GD
Lopaschuk
D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000378:metabolism*; D000107:Acetylation; D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D002460:Cell Line; D004734:Energy Metabolism; D005227:Fatty Acids / Q000378:metabolism*; D005318:Fetal Heart / Q000378:metabolism*; D006019:Glycolysis; D006593:Hexokinase / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D015151:Immunoblotting; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D008239:Lysine / Q000378:metabolism; D008929:Mitochondria, Heart / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism; D010736:Phosphoglycerate Mutase / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011817:Rabbits; D051381:Rats; D019802:Succinic Acid / Q000378:metabolism
D005227:Fatty Acids; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D000255:Adenosine Triphosphate; D019802:Succinic Acid; D015094:3-Hydroxyacyl CoA Dehydrogenases; D044942:Acyl-CoA Dehydrogenase, Long-Chain; D006593:Hexokinase; D010736:Phosphoglycerate Mutase; D008239:Lysine
lysine acetylation; lysine succinylation; myocardial fatty acid oxidation; newborn heart