Acetylation of mitochondrial proteins by GCN5L1 promotes enhanced fatty acid oxidation in the heart

Abstract

Lysine acetylation is a reversible posttranslational modification and is particularly important in the regulation of mitochondrial metabolic enzymes. Acetylation uses acetyl-CoA derived from fuel metabolism as a cofactor, thereby linking nutrition to metabolic activity. In the present study, we investigated how mitochondrial acetylation status in the heart is controlled by food intake and how these changes affect mitochondrial metabolism. We found that there was a significant increase in cardiac mitochondrial protein acetylation in mice fed a long-term high-fat diet and that this change correlated with an increase in the abundance of the mitochondrial acetyltransferase-related protein GCN5L1. We showed that the acetylation status of several mitochondrial fatty acid oxidation enzymes (long-chain acyl-CoA dehydrogenase, short-chain acyl-CoA dehydrogenase, and hydroxyacyl-CoA dehydrogenase) and a pyruvate oxidation enzyme (pyruvate dehydrogenase) was significantly upregulated in high-fat diet-fed mice and that the increase in long-chain and short-chain acyl-CoA dehydrogenase acetylation correlated with increased enzymatic activity. Finally, we demonstrated that the acetylation of mitochondrial fatty acid oxidation proteins was decreased after GCN5L1 knockdown and that the reduced acetylation led to diminished fatty acid oxidation in cultured H9C2 cells. These data indicate that lysine acetylation promotes fatty acid oxidation in the heart and that this modification is regulated in part by the activity of GCN5L1. Recent research has shown that acetylation of mitochondrial fatty acid oxidation enzymes has greatly contrasting effects on their activity in different tissues. Here, we provide new evidence that acetylation of cardiac mitochondrial fatty acid oxidation enzymes by GCN5L1 significantly upregulates their activity in diet-induced obese mice.

Cardiomyocyte-Specific Deletion of GCN5L1 in Mice Limits Ex Vivo Cardiac Functional Decline in Response to a High Fat Diet

“…Furthermore, we and others have shown that mitochondrial protein acetylation is significantly increased in various tissues during obesity [13][14][15][16]. Specifically in the heart, we have shown that an increase in acetylation results in increased activity of several FAO enzymes, which is regulated in part by the mitochondrial acetyltransferase GCN5L1 [16]. These findings place nutritional inputs, lysine acetylation, substrate utilization, and GCN5L1 at a key regulatory node in cardiac energy metabolism.…”

“…Pougovkina et al demonstrated that circulating free fatty acids, prevalent in obesity and diabetes, are the main source of acetyl-coA used for lysine acetylation [12]. Furthermore, we and others have shown that mitochondrial protein acetylation is significantly increased in various tissues during obesity [13][14][15][16]. Specifically in the heart, we have shown that an increase in acetylation results in increased activity of several FAO enzymes, which is regulated in part by the mitochondrial acetyltransferase GCN5L1 [16].…”

“…We have previously shown that prolonged high fat feeding leads to increased acetylation of mitochondrial proteins, which was in part regulated by GCN5L1 in vitro [16]. In order to further substantiate the role played by GCN5L1 in regulating this acetylation profile following exposure to a HFD, we utilized a newly-described GCN5L1 cKO animal model [19].…”

“…GCN5L1 is a mitochondrial matrix protein that has been shown to counter the activity of the mitochondrial deacetylase SIRT3. Specifically, it has been shown to regulate the acetylation of several mitochondrial FAO, glucose oxidation, and electron transport chain (ETC) proteins [15][16][17]. Loss of GCN5L1 has been shown to limit mitochondrial respiratory capacity [18], while increasing cardiac glucose utilization and reducing fatty acid utilization [16,19].…”

“…Specifically, it has been shown to regulate the acetylation of several mitochondrial FAO, glucose oxidation, and electron transport chain (ETC) proteins [15][16][17]. Loss of GCN5L1 has been shown to limit mitochondrial respiratory capacity [18], while increasing cardiac glucose utilization and reducing fatty acid utilization [16,19]. While the role of GCN5L1 in regulating FAO and glucose oxidation enzyme acetylation has been studied in vitro, it is not known whether cardiomyocyte-specific deletion of GCN5L1 results in decreased acetylation of mitochondrial proteins in response to a high fat diet (HFD) in vivo.…”