Metabolite

Energy source

Amino acid

Bacteria

Biology

Citric acid cycle

Glycolysis

Metabolic flux analysis

Anaerobic glycolysis

Endocrinology

Metabolism

Biochemistry

Coal

Metabolic pathway

Tricarboxylic acid

Genetics

Organic chemistry

Lactic acid

Internal medicine

Medicine

Chemistry

Flux (metallurgy)

Gluconeogenesis

Carbohydrate metabolism

Glutamine

Nature

Metabolic flux analysis in mice reveals that lactate often acts as the primary carbon source for the tricarboxylic acid cycle both in normal tissues and in tumour microenvironments. Glucose is thought to be the primary source of fuel for the tricarboxylic acid (TCA) cycle, also known as the citric acid cycle, which produces important metabolites and energy. Sheng Hui et al. now perform whole-body metabolite analysis in mice. They find that circulating lactate rather than glucose can be a major source of carbon and hence fuel for TCA metabolism in both fed and fasting mice. They furthermore show this to be the case in tumour tissue. Mammalian tissues are fuelled by circulating nutrients, including glucose, amino acids, and various intermediary metabolites. Under aerobic conditions, glucose is generally assumed to be burned fully by tissues via the tricarboxylic acid cycle (TCA cycle) to carbon dioxide. Alternatively, glucose can be catabolized anaerobically via glycolysis to lactate, which is itself also a potential nutrient for tissues1 and tumours2,3,4,5. The quantitative relevance of circulating lactate or other metabolic intermediates as fuels remains unclear. Here we systematically examine the fluxes of circulating metabolites in mice, and find that lactate can be a primary source of carbon for the TCA cycle and thus of energy. Intravenous infusions of 13C-labelled nutrients reveal that, on a molar basis, the circulatory turnover flux of lactate is the highest of all metabolites and exceeds that of glucose by 1.1-fold in fed mice and 2.5-fold in fasting mice; lactate is made primarily from glucose but also from other sources. In both fed and fasted mice, 13C-lactate extensively labels TCA cycle intermediates in all tissues. Quantitative analysis reveals that during the fasted state, the contribution of glucose to tissue TCA metabolism is primarily indirect (via circulating lactate) in all tissues except the brain. In genetically engineered lung and pancreatic cancer tumours in fasted mice, the contribution of circulating lactate to TCA cycle intermediates exceeds that of glucose, with glutamine making a larger contribution than lactate in pancreatic cancer. Thus, glycolysis and the TCA cycle are uncoupled at the level of lactate, which is a primary circulating TCA substrate in most tissues and tumours.

Glucose feeds the TCA cycle via circulating lactate