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Release of targeted p53 from the mitochondrion as an early signal during mitochondrial dysfunction
Citation:
GREEN, M. L., M. PISANO, R. A. PROUGH, AND T. B. KNUDSEN. Release of targeted p53 from the mitochondrion as an early signal during mitochondrial dysfunction . Miles Houslay (ed.), Cellular Signalling. ELSEVIER, AMSTERDAM, Holland, In Press:1-10, (2013).
Impact/Purpose:
Perturbation of mitochondrial DNA (mtDNA) function has been reported in tumors. Mitochondrial dysfunction can disrupt cellular energy and redox status, calcium (Ca2+) balance, and patterns of gene expression in many cell types. As such, signaling pathways linking mitochondrial function to nuclear events are important for cellular homeostasis. Although the role of mitochondrial-p53 is well described for a role in apoptosis, effects of p53 on mitochondrial biogenesis are less known. The present study has examined the effect of mitochondrial dysfunction and PK11195 activity on the release of mitochondrion-specific p53, which may be likened to a mammalian RTG stress response triggered by mitochondrial dysfunction. Pharmacologically active concentrations of PK11195 suppressed this pathway.
Description:
Increased accumulation of p53 tumor suppressor protein is an early response to low-level stressors. To investigate the fate of mitochondrial-sequestered p53, mouse embryonic fibroblast cells (MEFs) on a p53-deficient genetic background were transfected with p53-EGFP fusion protein led by a sense (m53-EGFP) or antisense (c53-EGFP) mitochondrial import signal. Rotenone exposure (100 nM, 1 h) triggered the translocation of m53-EGFP from the mitochondrion to the nucleus, thus shifting the transfected cells from a mitochondrial p53 to a nuclear p53 state. Antibodies for p53 serine phosphorylation or lysine acetylation indicated a different post-translational status of recombinant p53 in the nucleus and mitochondrion, respectively. These data suggest that cycling of p53 through the mitochondria may establish a direct pathway for p53 signaling from the mitochondria to the nucleus during mitochondrial dysfunction. PK11195, a pharmacological ligand of mitochondrial TSPO (formerly known as the peripheral-type benzodiazepine receptor), partially suppressed the release of mitochondria-sequestered p53. These findings support the notion that p53 function mediates a direct signaling pathway from the mitochondria to nucleus during mitochondrial dysfunction.
