Jiang P, Du W, Mancuso A et al.Reciprocal regulation of p53 and malic enzymes modulates metabolism and senescence. Nature 493:689-693

1] Department of Cancer Biology and Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA [2].
Nature (Impact Factor: 41.46). 01/2013; 493(7434). DOI: 10.1038/nature11776
Source: PubMed


Cellular senescence both protects multicellular organisms from cancer and contributes to their ageing. 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 understood. 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.

    • "Some studies implicate mitochondrial reactive oxygen species (ROS) as causal (Jiang et al., 2013b; Moiseeva et al., 2009; Passos et al., 2010; Velarde et al., 2012), but other outcomes of mitochondrial dysfunction are also likely. For example, sustained activation of 5 0 AMP-activated protein kinase (AMPK), a major bioenergetic sensor, is a hallmark of senescence (Moiseeva et al., 2009) and can induce a senescence arrest (Jiang et al., 2013b; Jones et al., 2005; Wang et al., 2003). Unlike the growth arrest and markers such as senescence-associated b-galactosidase (SA-Bgal) (Dimri et al., 1995), little is known about how mitochondria affect the SASP. "
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    ABSTRACT: Cellular senescence permanently arrests cell proliferation, often accompanied by a multi-faceted senescence-associated secretory phenotype (SASP). Loss of mitochondrial function can drive age-related declines in the function of many post-mitotic tissues, but little is known about how mitochondrial dysfunction affects mitotic tissues. We show here that several manipulations that compromise mitochondrial function in proliferating human cells induce a senescence growth arrest with a modified SASP that lacks the IL-1-dependent inflammatory arm. Cells that underwent mitochondrial dysfunction-associated senescence (MiDAS) had lower NAD+/NADH ratios, which caused both the growth arrest and prevented the IL-1-associated SASP through AMPK-mediated p53 activation. Progeroid mice that rapidly accrue mtDNA mutations accumulated senescent cells with a MiDAS SASP in vivo, which suppressed adipogenesis and stimulated keratinocyte differentiation in cell culture. Our data identify a distinct senescence response and provide a mechanism by which mitochondrial dysfunction can drive aging phenotypes. Wiley et al. show that mitochondrial dysfunction induces a senescence state termed MiDAS, causing a distinct secretion profile and mitotic arrest, which can be rescued with pyruvate. MiDAS is controlled by an NAD-AMPK-p53 pathway and occurs in progeroid mice, providing a basis for how dysfunctional mitochondria drive aging phenotypes.
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    • "Heterologous expression of M. circinelloides ME in R. glutinis also significantly promoted lipid accumulation (Li et al., 2013). Overexpression of ME enhanced tumor cell growth and depletion of ME strongly impaired tumor cell growth and quantity (Jiang et al., 2013). However, we found a slightly lower growth rate in PtMEoverexpressing P. tricornutum, which we believe was due to the over storage of lipid. "
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    ABSTRACT: To obtain fast growing oil-rich microalgal strains has been urgently demanded for microalgal biofuel. Malic enzyme (ME), which is involved in pyruvate metabolism and carbon fixation, was first characterized in microalgae here. Overexpression of Phaeodactylum tricornutum ME (PtME) significantly enhanced the expression of PtME and its enzymatic activity in transgenic P. tricornutum. The total lipid content in transgenic cells markedly increased by 2.5-fold and reached a record 57.8% of dry cell weight with a similar growth rate to wild type, thus keeping a high biomass. The neutral lipid content was further increased by 31% under nitrogen-deprivation treatment, still 66% higher than that of wild type. Transgenic microalgae cells exhibited obvious morphological changes, as the cells were shorter and thicker and contained larger oil bodies. Immuno-electron microscopy targeted PtME to the mitochondrion. This study markedly increased the oil content in microalgae, suggesting a new route for developing ideal microalgal strains for industrial biodiesel production.
    Full-text · Article · Oct 2014 · Metabolic Engineering
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    • "These data suggest that NSCs showed different alteration of p53 and cyclin E1 levels in response to a solution containing glucose or pH buffer system or not. The conflict that NSCs exposed to these different harvesting media displayed consistent proliferation inhibition but distinct molecular responses further illustrates that a constrained level of p53 and cyclin E1 is necessary to support normal cell growth [20], [26], [27]. "
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    ABSTRACT: Various solutions are utilized widely for the isolation, harvesting, sorting, testing and transplantation of neural stem cells (NSCs), whereas the effects of harvesting media on the biological characteristics and repair potential of NSCs remain unclear. To examine some of these effects, NSCs were isolated from cortex of E14.5 mice and exposed to the conventional harvesting media [0.9% saline (Saline), phosphate-buffered saline (PBS) or artificial cerebrospinal fluid (ACSF)] or the proliferation culture medium (PCM) for different durations at 4°C. Treated NSCs were grafted by in situ injection into the lesion sites of traumatic brain injury (TBI) mice. In vitro, harvesting media-exposed NSCs displayed time-dependent reduction of viability and proliferation. S phase entry decreased in harvesting media-exposed cells, which was associated with upregulation of p53 protein and downregulation of cyclin E1 protein. Moreover, harvesting media exposure induced the necrosis and apoptosis of NSCs. The levels of Fas-L, cleaved caspase 3 and 8 were increased, which suggests that the death receptor signaling pathway is involved in the apoptosis of NSCs. In addition, exposure to Saline did not facilitate the neuronal differentiation of NSCs, suggesting that Saline exposure may be disadvantageous for neurogenesis. In vivo, NSC-mediated functional recovery in harvesting media-exposed NSC groups was notably attenuated in comparison with the PCM-exposed NSC group. In conclusion, harvesting media exposure modulates the biological characteristics and repair potential of NSCs after TBI. Our results suggest that insight of the effects of harvesting media exposure on NSCs is critical for developing strategies to assure the successful long-term engraftment of NSCs.
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