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Reduced acetylation of TFAM promotes bioenergetic dysfunction in the failing heart by Manling Zhang; Ning Feng; Zishan Peng; Dharendra Thapa; Michael W. Stoner; Janet R. Manning; Charles F. McTiernan; Xue Yang; Michael J. Jurczak; Danielle Guimaraes; Krithika Rao; Sruti Shiva; Brett A. Kaufman; Michael N. Sack; Iain Scott is a Biochemistry, Genetics and Molecular Biology article available to read on EtoBox.

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## Summary General control of amino acid synthesis 5-like 1 (GCN5L1) was previously identified as a key regulator of protein lysine acetylation in mitochondria. Subsequent studies demonstrated that GCN5L1 regulates the acetylation status and activity of mitochondrial fuel substrate metabolism enzymes. However, the role of GCN5L1 in response to chronic hemodynamic stress is largely unknown. Here, we show that cardiomyocyte-specific GCN5L1 knockout mice (cGCN5L1 KO) display exacerbated heart failure progression following transaortic constriction (TAC). Mitochondrial DNA and protein levels were decreased in cGCN5L1 KO hearts after TAC, and isolated neonatal cardiomyocytes with reduced GCN5L1 expression had lower bioenergetic output in response to hypertrophic stress. Loss of GCN5L1 expression led to a decrease in the acetylation status of mitochondrial transcription factor A (TFAM) after TAC __in vivo__, which was linked to a reduction in mtDNA levels __in vitro__. Together, these data suggest that GCN5L1 may protect from hemodynamic stress by maintaining mitochondrial bioenergetic output.

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Author

Manling Zhang; Ning Feng; Zishan Peng; Dharendra Thapa; Michael W. Stoner; Janet R. Manning; Charles F. McTiernan; Xue Yang; Michael J. Jurczak; Danielle Guimaraes; Krithika Rao; Sruti Shiva; Brett A. Kaufman; Michael N. Sack; Iain Scott

Publisher

Elsevier BV

Published

2023

Language

EN

Field

Biochemistry, Genetics and Molecular Biology (Life Sciences)