GPER-dependent estrogen signaling increases cardiac GCN5L1 expression

Reversible lysine acetylation regulates the activity of cardiac metabolic enzymes, including those controlling fuel substrate metabolism. Mitochondrial-targeted GCN5L1 and SIRT3 have been shown to regulate the acetylation status of mitochondrial enzymes, but the role that lysine acetylation plays in...

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Bibliographic Details
Published in:American journal of physiology. Heart and circulatory physiology 2022-05, Vol.322 (5), p.H762-H768
Main Authors: Manning, Janet R, Thapa, Dharendra, Zhang, Manling, Stoner, Michael W, Sembrat, John C, Rojas, Mauricio, Scott, Iain
Format: Article
Language:English
Subjects:
Acetylation
Animals
Enzymes
Estrogen receptors
Estrogens
Female
Heart
Heart - physiology
Humans
Lysine
Male
Males
Metabolism
Mice
Mitochondria
Mitochondrial Proteins - metabolism
Nerve Tissue Proteins - metabolism
Rapid Report
Sirtuin 3 - genetics
Sirtuin 3 - metabolism
Substrates
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Summary:Reversible lysine acetylation regulates the activity of cardiac metabolic enzymes, including those controlling fuel substrate metabolism. Mitochondrial-targeted GCN5L1 and SIRT3 have been shown to regulate the acetylation status of mitochondrial enzymes, but the role that lysine acetylation plays in driving metabolic differences between male and female hearts is not currently known. In this study, we describe a significant difference in GCN5L1 levels between male and female mouse hearts, and in the hearts of women between post- and premenopausal age. We further find that estrogen drives GCN5L1 expression in a cardiac cell line and uses pharmacological approaches to determine the mechanism to be G protein-coupled estrogen receptor (GPER) activation, via translational regulation. We demonstrate here for the first time that mitochondrial protein acetylation is increased in female hearts, associated with an increase in GCN5L1 levels through a GPER-dependent mechanism. These findings reveal a new potential mediator of divergent cardiac mitochondrial function between men and women.
ISSN:0363-6135
1522-1539
DOI:10.1152/ajpheart.00024.2022