Abstract
SummaryReactive aldehydes arise as by-products of metabolism and are normally cleared by multiple families of enzymes. We find that mice lacking two aldehyde detoxifying enzymes, mitochondrial ALDH2 and cytoplasmic ADH5, have greatly shortened lifespans and develop leukemia. Hematopoiesis is disrupted profoundly, with a reduction of hematopoietic stem cells and common lymphoid progenitors causing a severely depleted acquired immune system. We show that formaldehyde is a common substrate of ALDH2 and ADH5 and establish methods to quantify elevated blood formaldehyde and formaldehyde-DNA adducts in tissues. Bone-marrow-derived progenitors actively engage DNA repair but also imprint a formaldehyde-driven mutation signature similar to aging-associated human cancer mutation signatures. Furthermore, we identify analogous genetic defects in children causing a previously uncharacterized inherited bone marrow failure and pre-leukemic syndrome. Endogenous formaldehyde clearance alone is therefore critical for hematopoiesis and in limiting mutagenesis in somatic tissues.
Highlights
Reactive chemistry drives many fundamental metabolic processes of life
Aged Aldh2À/ÀAdh5À/À mice continued to remain considerably smaller than wild-type littermate controls, and none lived longer than 47 weeks
Combined inactivation of the aldehyde-clearing enzymes ALDH2 and ADH5 leads to perinatal lethality, growth failure, lymphopenia, and lymphoid malignancies
Summary
Reactive chemistry drives many fundamental metabolic processes of life. The reactive metabolites involved are often toxic because they can inappropriately attack cellular constituents, driving degenerative changes associated with aging and carcinogenesis. The best-studied group of such molecules are reactive oxygen species (ROS), which have been implicated in a wide range of (patho)physiological processes. A new and emerging group of reactive metabolites are endogenous aldehydes, and the threat they pose, combined with their molecular diversity, could explain why we possess so many enzymes to detoxify them. There are at least 19 distinct aldehyde dehydrogenases (ALDHs) as well as a number of enzymes that process aldehyde-glutathione conjugates (glutathione S-transferases [GSTs] and ADH5) (Jackson et al, 2011). We understand very little about the physiological importance of different aldehydes, which enzymes metabolize them, and whether these detoxifying enzymes are functionally linked to one another
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