Heritable shifts in redox metabolites during mitochondrial quiescence reprogram progeny metabolism

Changes in maternal diet and metabolic defects in mothers can profoundly impact progeny health and disease. However, the biochemical mechanisms that induce the initial reprogramming events at the cellular level have remained largely unknown due to limitations in obtaining pure populations of quiescent oocytes. Here, we show that the precocious onset of Mitochondrial Respiratory Quiescence (MRQ) causes a reprogramming of progeny metabolic state. The premature onset of MRQ drives the lowering of Drosophila oocyte NAD+ levels. NAD+ depletion in the oocyte leads to reduced methionine cycle production of the methyl donor S-adenosylmethionine (SAM) in embryos and lower H3K27-me3 levels, resulting in enhanced levels of progeny intestinal lipid metabolism. In addition, we show that triggering cellular quiescence in mammalian cells and chemotherapy-resistant human cancer cell models induces cellular reprogramming events identical to those seen in Drosophila, suggesting a conserved metabolic mechanism in systems reliant on quiescent cells.