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2017 ; 551
(7678
): 115-118
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Glucose feeds the TCA cycle via circulating lactate
#MMPMID29045397
Hui S
; Ghergurovich JM
; Morscher RJ
; Jang C
; Teng X
; Lu W
; Esparza LA
; Reya T
; Le Zhan
; Yanxiang Guo J
; White E
; Rabinowitz JD
Nature
2017[Nov]; 551
(7678
): 115-118
PMID29045397
show ga
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 tissues and tumours. 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 (13)C-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, (13)C-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.
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