p53-Dependent Regulation of Mitochondrial Energy Production by the RelA Subunit of NF-κB

Abstract

Aberrant activity of the nuclear factor kappaB (NF-kB) transcription factor family, which regulates cellular responses to stress and infection, is associated with many human cancers. In this study, we define a function of NF-kB in regulation of cellular respiration that is dependent upon the tumor suppressor p53. Translocation of the NF-kB family member RelA to mitochondria was inhibited by p53 by blocking an essential interaction with the HSP Mortalin. However, in the absence of p53, RelA was transported into the mitochondria and recruited to the mitochondrial genome where it repressed mitochondrial gene expression, oxygen consumption, and cellular ATP levels. We found mitochondrial RelA function to be dependent on its conserved C-terminal transactivation domain and independent of its sequence-specific DNA-binding ability, suggesting that its function in this setting was mediated by direct interaction with mitochondrial transcription factors. Taken together, our findings uncover a new mechanism through which RelA can regulate mitochondrial function, with important implications for how NF-kB activity and loss of p53 can contribute to changes in tumor cell metabolism and energy production. Cancer Res; 71(16); 5588-97. Ó2011 AACR.

Oleate prevents palmitate-induced mitochondrial dysfunction, insulin resistance and inflammatory signaling in neuronal cells

“…Increased PGC-1α expression and decreased NF-κB activation following oleate treatment were attributed to enhanced peroxisome proliferator-activated receptor (PPAR) and protein kinase A activation in skeletal muscle [28]. Since the NF-κB pathway is involved in the regulation of PGC-1α [7] and in mitochondrial gene expression [53], our finding that oleate reduced NF-κB signaling may be linked to a sustained rise in PGC-1α. Increased PGC-1α may therefore play an important role in the protective effect of oleate against palmitate-induced mitochondrial dysfunction in neurons as in muscle [27].…”

Mitochondrial uncoupling protein (UCP2) gene expression is regulated by miR-2909

“…Recent findings have established that AATF genome encoded miR-2909 not only requires nuclear RelA translocation for its expression but also this microRNA regulates gene expression through repression of KLF4 gene expression resulting in the up-regulation of SP1 gene expression [7,8]. At this stage, it is pertinent to note that: a) SP1 has been shown to induce genes coding for AATF, CCL5 and p53 [13][14][15]; b) p53 gene expression is also induced by CCL5 and AATF-dependent translocation of RelA to p53 gene promoter [6,16]; c) KLF4 has been shown to induce IL-17 gene expression [12] and p53 binds RelA to block its translocation either to nucleus or mitochondria [4]; d) KLF4 is known to repress Bmi-1 gene which is known to degrade the p53 protein [17,18]. The results reported here together with above-mentioned findings in the literature, led us to the mechanism which reveals as to how AATF RNome can regulate UCP2 gene in a cyclic fashion (Fig.…”

“…Several findings have suggested that mitochondrial uncoupling protein (UCP2) initiates aerobic-glycolysis by shunting pyruvate out of mitochondria through decoupling of glycolysis from aerobic respiration [3]. However, translocation of the NFκB family member RelA to mitochondria was also shown to initiate aerobic-glycolysis and this translocation was inhibited by p53 [4]. In this context, it is interesting to note that AATF was not only shown to ameliorate mitochondrial dysfunction coupled with accumulation of superoxide/peroxynitrite [5] but also had the capacity to induce p53 expression through its interaction with RelA [6].…”

The Metabolic Effects of Traditional Chinese Medication Qiliqiangxin on H9C2 Cardiomyocytes

“…PGC-1α is a key regulator participating in mitochondrial biogenesis and oxidative metabolism in the heart [11]. Besides that, PGC-1α also induces mitochondrial replication by increasing the expression levels of mitochondria-related genes, such as mitochondrial transcription factor A (TFAM), single strand binding protein (SSBP) and transcription factor B2 (TFB2M) [12,13]. Several reports have demonstrated that mitochondrial function is increased by activating PGC-1α [14,15].…”