Reduced acetylation of TFAM promotes bioenergetic dysfunction in the failing heart

Zhang, M.; Feng, N.; Thapa, D.; Stoner, M. W.; Manning, J. R.; McTiernan, C. F.; Yang, X.; Peng, Z.; Jurczak, M. J.; Guimaraes, D.; Shiva, S.; Kaufman, B. A.; Sack, M. N.; Scott, I.

doi:10.1101/2022.10.31.514513

bioRxiv · 10.1101/2022.10.31.514513

Reduced acetylation of TFAM promotes bioenergetic dysfunction in the failing heart

Zhang, M.·Feng, N.·Thapa, D.·Stoner, M. W.·Manning, J. R.·McTiernan, C. F.·Yang, X.·Peng, Z.·Jurczak, M. J.·Guimaraes, D.·Shiva, S.·Kaufman, B. A.·Sack, M. N.·Scott, I.

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Abstract

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 pressure overload-induced heart failure progression following transaortic constriction (TAC). Mitochondrial DNA and mitochondrial electron transport chain 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. HighlightsO_LIReduced GCN5L1 expression in the failing heart promotes contractile dysfunction C_LIO_LIMitochondrial DNA (mtDNA) levels are reduced in cardiomyocyte-specific GCN5L1 knockout mice following hemodynamic stress C_LIO_LIGCN5L1 knockdown reduces, and GCN5L1 overexpression increases, bioenergetic output in hypertrophic cardiomyocytes C_LIO_LIGCN5L1-mediated acetylation of TFAM promotes increased mtDNA levels C_LI

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Zhang, M., Feng, N., Thapa, D., Stoner, M. W., Manning, J. R., McTiernan, C. F., Yang, X., Peng, Z., Jurczak, M. J., Guimaraes, D., Shiva, S., Kaufman, B. A., Sack, M. N., Scott, I.. 2022-11-01. Reduced acetylation of TFAM promotes bioenergetic dysfunction in the failing heart. https://doi.org/10.1101/2022.10.31.514513

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