Direct influence of the p53 tumor suppressor on mitochondrial biogenesis and function

Mitochondrial localization of p53 has been observed in several cell systems , but an understanding of its organelle-based physiological activity remain s incomplete. The purpose of the present study was to investigate the mitoc hondrial DNA genomic response to dominant-negative p53 mutant miniprotein ( p53DD) fused to a mitochondrial import signal. Constructs were generated to express mitochondrial targeted enhanced green fluorescent protein (mEGFP) or dominant-negative mutant p53 miniprotein (m53DD) by in-frame fusion to t he signal peptide sequence of murine Cox8l. Control cytosolic vectors (cEGF P, c53DD) had the signal sequence placed in antisense orientation. NIH 3T3 cells were transiently transfected with these vectors in various combinatio ns. Mitochondrial 16S ribosomal RNA (16S rRNA) expression and fluorochrome staining with Mitotracker Red CMXRos (Delta Psim) were decreased in cells e xpressing m53DD, Both alterations were specific for mitochondrial import co mpetence (e.g., m53DD vs. c53DD) as well as the passenger protein (e.g., m5 3DD vs. mEGFP). The normal functional state of mitochondria was restored wi th PK11195, a specific ligand of the mitochondrial peripheral-type benzodia zepine receptor. Negative dominance of m53DD on 16S rRNA expression and CMX Ros staining, and rescue of these parameters with PK11195, imply a direct p ositive effect of p53 on mitochondrial biogenesis and function.-Donahue, R. J., Razmara, M., Hock, J. B., Knudsen, T. B. Direct influence of the p53 t umor suppressor on mitochondrial biogenesis and function.