Acetate Production from Glucose and Coupling to Mitochondrial Metabolism in Mammals

Autor(es):Mostrar menos -

Liu, Xiaojing ^[1] ; Cooper, Daniel E. ^[2] ; Cluntun, Ahmad A. ^[1] ; Warmoes, Marc O. ^[1] ; Zhao, Steven ^[3] ; Reid, Michael A. ^[1] ; Liu, Juan ^[1] ; Lund, Peder J. ^[4] ; Lopes, Mariana ^[4] ; Garcia, Benjamin A. ^[4] ; Wellen, Kathryn E. ^[3] ; Kirsch, David G. ^{[1, 2]} ; Locasale, Jason W. ^[1]

Afiliação do(s) autor(es)

^[1] Duke Univ, Sch Med, Dept Pharmacol & Canc Biol, Durham, NC 27710 - USA

^[2] Duke Univ, Dept Radiat Oncol, Med Ctr, Durham, NC 27710 - USA

^[3] Univ Penn, Perelman Sch Med, Dept Canc Biol, Philadelphia, PA 19104 - USA

^[4] Univ Penn, Perelman Sch Med, Penn Epigenet Inst, Dept Biochem & Biophys, Philadelphia, PA 19104 - USA

• Tipo de documento: Artigo Científico
• Fonte: Cell; v. 175, n. 2, p. 502+, OCT 4 2018.
• Citações Web of Science: 21

Resumo

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. (AU)

• Processo FAPESP: 17/15835-1 - Integração entre vias de sinalização e modificações pós traducionais em histonas em resposta a fator de crescimento
• Beneficiário: Mariana de Camargo Lopes
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado Direto