Release of targeted p53 from the mitochondrion as an early signal during mitochondrial dysfunction

• Published in: Cellular signalling 2013-12, Vol.25 (12), p.2383-2390
• Main Authors: Green, M.L., Pisano, M.M., Prough, R.A., Knudsen, T.B.
• Format: Article
• Language: English
• Subjects: Animals; Cell Line; Embryo; Fibroblasts - drug effects; Fibroblasts - metabolism; Fibroblasts - pathology; Gene Deletion; Isoquinolines - pharmacology; Mice; Mitochondria; Mitochondria - genetics; Mitochondria - metabolism; Mitochondria - pathology; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; p53; PK11195; Protein Transport - drug effects; Rotenone; Rotenone - pharmacology; Signal Transduction - drug effects; Transfection; TspO; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2013.07.019

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 (100nM, 1h) 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. •p53 tumor suppressor protein accumulation is an early response to low-level stressors.•p53-null MEFs were transfected with mitochondria-p53 (m53-EGFP) fusion protein.•Rotenone triggered m53-EGFP translocation from mitochondrion to nucleus.•PK11195 partially suppressed p53 translocation and posttranslational modifications.•p53 function mediates a direct signaling pathway during mitochondrial dysfunction.