Our cells’ mitochondria use several different pathways to transform the nutrients we consume into energy in the form of ATP (adenosine triphosphate). One of those pathways—fatty acid oxidation (FAO)—is essential for the self-renewal of hematopoietic (blood-forming) stem cells (HSCs). However, the precise mechanism by which mitochondrial metabolism governs HSC fate has remained elusive.

In a study published online on March 7 in Cell Stem Cell, Keisuke Ito, M.D., Ph.D., and colleagues showed that FAO oxidation in the mitochondria of HSCs produces large amounts of NADPH (nicotinamide adenine dinucleotide phosphate) and that these high levels of mitochondrial NADPH levels are crucial for keeping HSCs healthy and able to renew themselves. More specifically, the pool of NADPH in HSCs supports two fundamental processes: cholesterol biosynthesis and the production of extracellular vesicles, which help to maintain HSCs and facilitate cell-to-cell communication.

The study revealed that mitochondrial metabolism helps to steer the “fate decisions” made by HSCs, i.e., whether to self-renew or to differentiate into specialized blood cells. The findings could lead to the development of therapies for blood-disorders, in which mitochondrial metabolism might be targeted to enhance the functioning of HSCs.

Dr. Ito is professor of cell biology, of medicine, and of oncology, director of scientific resources of the Ruth L. and David S. Gottesman Institute for Stem Cell Biology and Regenerative Medicine at Einstein, and a member of the National Cancer Institute–designated Montefiore Einstein Comprehensive Cancer Center.