Reduced acetylation of TFAM promotes bioenergetic dysfunction in the failing heart

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

doi:10.1016/j.isci.2023.106942

Reduced acetylation of TFAM promotes bioenergetic dysfunction in the failing heart

iScience. 2023 May 23;26(6):106942. doi: 10.1016/j.isci.2023.106942. eCollection 2023 Jun 16.

Authors

Manling Zhang^{1

2

3}, Ning Feng^{1

2

3}, Zishan Peng^{1

2}, Dharendra Thapa⁴, Michael W Stoner^{1

2

5}, Janet R Manning^{1

2

5}, Charles F McTiernan^{1

2}, Xue Yang^{1

2}, Michael J Jurczak^{5

6}, Danielle Guimaraes^{1

2

7}, Krithika Rao^{1

2

7}, Sruti Shiva^{1

2

7}, Brett A Kaufman^{1

2

5}, Michael N Sack⁸, Iain Scott^{1

2

5}

Affiliations

¹ Vascular Medicine Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
² Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
³ Pittsburgh Veteran Affairs Medical Center, Pittsburgh, PA 15240, USA.
⁴ Division of Exercise Physiology, West Virginia University School of Medicine, Morgantown, WV 26506, USA.
⁵ Center for Metabolism and Mitochondrial Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
⁶ Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
⁷ Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
⁸ Intramural Research Program, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA.

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 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.

Keywords: Hematology; Molecular biology; Physiology.

Abstract

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