Reciprocal regulation of p53 and malic enzymes modulates metabolism and senescence

Abstract

Evidence for a link between cellular senescence and metabolic regulation is provided, through the observation that p53 represses the expression of malic enzymes, thereby regulating NADPH, lipid and glutamine metabolism; in turn, this repression further activates p53, promoting cellular senescence. The tumour suppressor p53 is known to regulate metabolic processes as well as cellular senescence. Peng Jiang et al. now link the two activities, showing that p53 represses the expression of the malic enzymes ME1 and ME2 and thereby regulates NADPH production, lipid and glutamine metabolism. ME1 and ME2 downregulation can, in turn, further activate p53 and thereby promote cellular senescence. ME1 and ME2 are often overexpressed in cancers and can suppress senescence and promote tumour growth. Cellular senescence both protects multicellular organisms from cancer and contributes to their ageing1. The pre-eminent tumour suppressor p53 has an important role in the induction and maintenance of senescence, but how it carries out this function remains poorly understood1,2,3. In addition, although increasing evidence supports the idea that metabolic changes underlie many cell-fate decisions and p53-mediated tumour suppression, few connections between metabolic enzymes and senescence have been established. Here we describe a new mechanism by which p53 links these functions. We show that p53 represses the expression of the tricarboxylic-acid-cycle-associated malic enzymes ME1 and ME2 in human and mouse cells. Both malic enzymes are important for NADPH production, lipogenesis and glutamine metabolism, but ME2 has a more profound effect. Through the inhibition of malic enzymes, p53 regulates cell metabolism and proliferation. Downregulation of ME1 and ME2 reciprocally activates p53 through distinct MDM2- and AMP-activated protein kinase-mediated mechanisms in a feed-forward manner, bolstering this pathway and enhancing p53 activation. Downregulation of ME1 and ME2 also modulates the outcome of p53 activation, leading to strong induction of senescence, but not apoptosis, whereas enforced expression of either malic enzyme suppresses senescence. Our findings define physiological functions of malic enzymes, demonstrate a positive-feedback mechanism that sustains p53 activation, and reveal a connection between metabolism and senescence mediated by p53.