Biosacetalin 1,1-Diethoxyethane enhances aerobic respiration via activation of AMP-activated protein kinase

The enzyme 5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a key regulator of cellular energy metabolism, playing a protective role in cardiovascular remodeling and diseases. Here, 1,1-Diethoxyethane (1,1-DEE), a compound traditionally known as a flavoring agent in wine and distilled spirits, was identified as an AMPK activator. By analyzing AC16 cardiomyocytes with the Seahorse Mito Stress Test, we found that 1,1-DEE induced a transient inhibition of both mitochondrial respiration and glycolysis, resulting in reduced ATP production. This metabolic disturbance triggered AMPK activation in a time- and concentration-dependent manner, leading to adaptive increases in the phosphorylation of acetyl-CoA carboxylase and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2, which promotes fatty acid oxidation and glycolysis. AMPK activation also enhanced mitochondrial biogenesis by upregulating peroxisome proliferator-activated receptor gamma coactivator 1-alpha and mitochondrial transcription factor A. These alterations led to a sustained increase in both mitochondrial respiration and glycolysis. Overall, our findings unravel the important physiological role of 1,1-DEE in energy homeostasis through AMPK activation and aerobic respiration. This mechanism may hold therapeutic potential for the prevention and treatment of metabolic and cardiovascular diseases. Overall design: RNA-seq of profiling of heart tissues of C57BL/6J mice (normal diet (ND) group and 1,1-DEE-treated group) after 8 weeks of treatment.