Stem cell function in vivo is supported by an alternative glycolysis endpoint

Area of Science:

• Cellular metabolism
• Stem cell biology
• Biochemistry

Background:

• Carbohydrate catabolism typically occurs via fermentation or oxidation, impacting cell proliferation.
• Proliferating cells, including stem and progenitor cells, often favor fermentation and lactate production in vitro.
• The necessity of oxidation or fermentation as terminal carbohydrate fates in vivo has not been tested due to the lack of simultaneous key enzyme deletions.

Purpose of the Study:

• To investigate whether carbohydrate oxidation and fermentation are obligatory for hematopoietic stem cell (HSC) survival and function in vivo.
• To determine the role of lactate dehydrogenase (LDH) and pyruvate dehydrogenase (PDH) in HSC metabolism.
• To identify alternative carbohydrate catabolic pathways in HSCs.

Main Methods:

• Simultaneous genetic deletion of key enzymes involved in carbohydrate metabolism: lactate dehydrogenase A/B (LDHA/B) and pyruvate dehydrogenase (PDH) in mice.
• Assessment of HSC survival, function, and glycolytic pathway termination.
• Analysis of pyruvate export and its dependence on the monocarboxylate transporter 1 (MCT1).

Main Results:

• Combined deletion of LDHA/B and PDH did not impair HSC survival or function, indicating dispensability of both fermentation and oxidation.
• HSCs lacking LDH and PDH preserved glycolysis, terminating it via pyruvate export.
• Pyruvate export was identified as a physiological response to nutrient levels and essential for HSC function, as demonstrated by impaired function upon MCT1 deletion.

Conclusions:

• In vivo carbohydrate metabolism in HSCs does not obligatorily require oxidation or fermentation, contrary to classical theories and in vitro observations.
• Pyruvate export represents a sufficient alternative pathway for terminating glycolysis and supporting stem cell function.
• The primary role of glycolysis termination in HSCs is pyruvate removal rather than acetyl-CoA production or lactate formation.