Acss1, or Acetyl-CoA synthetase short-chain family member 1, is a key enzyme that uses acetate to generate mitochondrial acetyl-CoA. It plays a crucial role in energy production through the tricarboxylic acid (TCA) cycle and is involved in lipid synthesis, protein acetylation, and metabolic regulation [1,5,6]. Genetic models, such as mouse models, are valuable for studying its functions.

In Acss1-K635Q knock-in mice, a mutation mimicking acetylation at lysine 635, there are significant metabolic changes. These mice show higher metabolic rates, increased blood acetate, and decreased liver/serum ATP and lactate levels. After fasting, they develop features of non-alcoholic fatty liver disease (NAFLD), including liver enlargement, lipid droplet accumulation, and microsteatosis. RNA sequencing reveals dysregulation of fatty acid metabolism, cellular senescence, and hepatic steatosis networks. Also, on a ketogenic diet, Acss1K635Q mice display more prominent liver steatosis and altered lipid profiles [1,5]. In cancer, ACSS1-dependent acetate metabolism rewires mitochondrial metabolism to support AML and melanoma tumor growth and metastasis, and its knockdown reduces leukemia burden in vivo and inhibits melanoma growth [2]. In a chronic sleep fragmentation mouse model, astrocyte-specific Acss1 deletion affects acetate levels, mitigating metabolic and cognitive impairments [3]. In sarcopenia models, Acss1 is identified as a key regulator and potential biomarker, showing a negative correlation with gastrocnemius weight [4].

In conclusion, Acss1 is essential for mitochondrial acetate metabolism and energy production. Studies using mouse models, especially knock-in and deletion models, have revealed its significant roles in diseases such as NAFLD, cancer, and sarcopenia, as well as in sleep-related metabolic and cognitive functions. Understanding Acss1 function provides insights into the underlying mechanisms of these diseases and potential therapeutic targets.