A pivotal role for p53: Balancing aerobic respiration and glycolysis

Cardiology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Journal of Bioenergetics (Impact Factor: 3.21). 07/2007; 39(3):243-6. DOI: 10.1007/s10863-007-9083-0
Source: PubMed


The genetic basis of increased glycolytic activity observed in cancer cells is likely to be the result of complex interactions of multiple regulatory pathways. Here we review the recent evidence of a simple genetic mechanism by which tumor suppressor p53 regulates mitochondrial respiration with secondary changes in glycolysis that are reminiscent of the Warburg effect. The biological significance of this regulation of the two major pathways of energy generation by p53 remains to be seen.

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    • "p53 is a transcription factor that serves as a regulator of various cellular processes including cellular energy metabolism. p53 plays a crucial role in cellular energy metabolism by balancing between OXPHOS and glycolysis (Ma et al., 2007). The combination of the transcription factors p53, c-Myc and HIF1 has been described as the " triad " of transcription factors responsible for the glycolytic phenotype seen in cancerous cell (Yeung et al., 2008). "
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    ABSTRACT: All forms of life share a common indispensible need of energy. The requirement of energy is necessary for an organism not only to survive but also to thrive. The metabolic activities in normal cells rely predominately on mitochondrial oxidative phophorylation for energy generation in the form of ATP. On the contrary, cancer cells predominately rely on glycolysis rather than oxidative phosphorylation. It is long believed that an impairment of mitochondrial oxidative phosphorylation is the cause of this glycolytic phenotype observed in cancers. However, studies in cancer metabolism have revealed that mitochondrial function in many cancers is intact. It has also been observed that cancers utilize various forms of metabolism. The various metabolic phenotypes are employed by cancer cells have a common purpose, to balance macromolecular biosynthesis and sufficient ATP production in order to support the rapid proliferation rate characteristic of these aberrant cells. These metabolic pathways are attractive targets for possible therapeutic interventions and currently research is underway to meet this end. More importantly, normal cells have essentially the same metabolic requirements as cancer cells so finding an approach to target these metabolic pathways without incurring detrimental effects on normal tissues remain the challenge.
    Mitochondrion 06/2014; 17. DOI:10.1016/j.mito.2014.05.010 · 3.25 Impact Factor
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    • "The aerobic use of glucose as an energy source through glycolysis is a feature common to most solid tumors and, in turn, leads to a lesser dependence on OXPHOS, called the Warburg effect (Pedersen, 1978; Racker and Spector, 1981). Downregulation of OXPHOS in tumor cells is achieved by the following mechanisms, among others: (1) lack of vascularization in rapidly growing tumors leads to profound hypoxia, which causes a compensatory upregulation of glycolysis in tumors; (2) genetic inactivation of regulators of OXPHOS, for example, the von Hippel Lindau (VHL) (Kley et al., 1995) and p53 (Bogler et al., 1995) genes, or activation of oncogenes can cause a secondary decrease in OXPHOS (Ma et al., 2007; Matoba et al., 2006; Zhang et al., 2007); and (3) direct loss of function of components of OXPHOS. Such loss of function has been demonstrated for pheochromocytomas and paragangliomas, which frequently exhibit mutations in genes encoding different subunits of succinate dehydrogenase (SDH; complex II), indicating that SDH subunits act as tumor suppressors in neuroendocrine tissues (Astuti et al., 2001; Brauch et al., 1997; Favier et al., 2009). "
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    ABSTRACT: The shift in cellular energy production from oxidative phosphorylation (OXPHOS) to glycolysis, even under aerobic conditions, called the Warburg effect, is a feature of most solid tumors. The activity levels of OXPHOS complexes and citrate synthase were determined in astrocytomas. A gradual decrease of citrate synthase and OXPHOS complexes was observed depending on tumor grade. In low-grade astrocytomas (WHO grade II), enzyme activities of citrate synthase, complex I, and complex V were comparable to those of normal brain tissue. A trend to reduced activities was observed for complexes II-IV. In glioblastoma (WHO grade IV), activities of citrate synthase and complexes I-IV were decreased by 56-92% as compared with normal brain. Immunohistochemical staining for porin revealed that the tumorpil of low-grade astrocytomas displays characteristics of the mitochondria-rich neuropil of normal brain tissue. In high-grade tumors (WHO grades III and IV), the tumorpil was characterized by severe morphologic alterations as well as loss of "pilem" structures. Specific alterations of OXPHOS complexes were observed in all astrocytic tumors by immunohistochemical analysis: 80% of astrocytomas exhibited severe deficiency of complex IV; complex I showed a gradual reduction in amount with increasing tumor grade, whereas complex II showed reduced levels only in high-grade (WHO grade IV) tumors (9/12); complexes III and V did not show significant alterations compared with normal brain tissue. OXPHOS defects were present not only in the cell bodies of tumor cells but also in the pilem structures, indicating that the ramifications/protuberances (tumorpil) in general originate from tumor cells. GLIA 2014.
    Glia 04/2014; 62(4). DOI:10.1002/glia.22621 · 6.03 Impact Factor
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    • "ARF, an upstream regulator of p53, also enhances autophagy, and ATG7, a core autophagy regulator, induces p21 via activating p53 through physical interaction, leading to cell survival during nutrient deprivation K. Itahana and S. Pervaiz p53 also induces autophagy by activating the transcription of DRAM gene, which encodes a lysosomal protein (Crighton et al. 2006 ). Other p53 target genes that mediate the induction of autophagy include sestrin-2 (Budanov and Karin 2008 ; Maiuri et al. 2009 ), autophagy-initiation kinases ULK1 and ULK2 (Gao et al. 2011 ), Dapk1 (Martoriati et al. 2005 ; Harrison et al. 2008 ), several well-known pro-apoptotic Bcl-2 family genes, such as Puma (Yee et al. 2009 ), Bax (Yee et al. 2009 ), and Bad (Maiuri et al. 2007 ), in addition to BNIP3 (Fei et al. 2004 ), whose product induces selective mitochondrial autophagy by competing with Beclin 1 for binding to Bcl2, thereby releasing Beclin 1 to trigger autophagy (Zhang et al. 2008 ). Furthermore, mitogen-activated protein kinase (MAPK) family proteins, such as extracellular signal-related kinase (ERK) and c-Jun N-terminal kinase (JNK), induce autophagy through p53 activation (Cheng et al. 2008 ; Park et al. 2009b ). "
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    ABSTRACT: After being obtained from bacteria, eukaryotic mitochondria acquired a myriad of metabolic functions during evolution to coordinate energy efficiency and demand with host cells during cell proliferation and growth arrest for maintaining cellular homeostasis as well as functions in decisions of cell death and survival. To achieve this, mitochondria and host cells have developed tight communications, and recent evidence suggests that tumour suppressor p53 actively participates in these communications. p53 influences mitochondrial metabolism by activating or repressing the transcription of target genes as well as directly interacting with proteins in different cellular compartments, including mitochondria. This review discusses recent findings of p53-mediated regulation of cellular metabolism, such as oxidative phosphorylation, glutamine and fatty acid metabolism, autophagy, glycolysis, and reactive oxygen species, to better understand the tumour suppressive functions of p53, which may facilitate the identification of novel therapeutic targets and strategies. © 2014 Springer Science+Business Media Dordrecht. All rights are reserved.
    Mitochondria: The anti-cancer target for the third millennium, Edited by Neuzil J, Pervaiz S, Fluda S, 04/2014: chapter Chapter 12: pages 327-348; Springer.
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