期刊
CELL
卷 175, 期 2, 页码 502-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2018.08.040
关键词
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资金
- NIH [R01CA193256, R00 CA16899, T32 CA093240, R35 CA197616, R01CA174761, R01GM110174, T32CA009140, F99CA222741]
- American Cancer Society [TBE434120, TBE130927]
- FAPESP [2017/15835-1]
- King Abdullah International Medical Research Center under the Ministry of National Guard Health graduate fellowship
Acetate is a major nutrient that supports acetylcoenzyme A (Ac-CoA) metabolism and thus lipogenesis and protein acetylation. However, its source is unclear. Here, we report that pyruvate, the end product of glycolysis and key node in central carbon metabolism, quantitatively generates acetate in mammals. This phenomenon becomes more pronounced in the context of nutritional excess, such as during hyperactive glucose metabolism. Conversion of pyruvate to acetate occurs through two mechanisms: (1) coupling to reactive oxygen species (ROS) and (2) neomorphic enzyme activity from keto acid dehydrogenases that enable function as pyruvate decarboxylases. Further, we demonstrate that de novo acetate production sustains Ac-CoA pools and cell proliferation in limited metabolic environments, such as during mitochondrial dysfunction or ATP citrate lyase (ACLY) deficiency. By virtue of de novo acetate production being coupled to mitochondrial metabolism, there are numerous possible regulatory mechanisms and links to pathophysiology.
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