Format

Send to

Choose Destination
Cell. 2018 Oct 4;175(2):502-513.e13. doi: 10.1016/j.cell.2018.08.040. Epub 2018 Sep 20.

Acetate Production from Glucose and Coupling to Mitochondrial Metabolism in Mammals.

Author information

1
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Duke University, Durham, NC 27710, USA.
2
Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA.
3
Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
4
Department of Biochemistry and Biophysics, Penn Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
5
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Duke University, Durham, NC 27710, USA; Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA.
6
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Duke University, Durham, NC 27710, USA. Electronic address: jason.locasale@duke.edu.

Abstract

Acetate is a major nutrient that supports acetyl-coenzyme 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.

KEYWORDS:

dehydrogenase; flux analysis; glycolysis; lipogenesis; metabolomics; mitochondria; pyruvate; reactive oxygen species; stable isotope tracing; thiamine

Comment in

PMID:
30245009
PMCID:
PMC6173642
DOI:
10.1016/j.cell.2018.08.040
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center