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Department of Pathology, Anatomy and Cell Biology, Jefferson Medical College, Philadelphia, Pennsylvania 19107, USA
1Correspondence: Department of Pathology, Anatomy and Cell Biology, Jefferson Medical College, 1020 Locust St., Philadelphia PA 19107, USA. E-mail: Thomas.Knudsen{at}mail.tju.edu
Mitochondrial localization of p53 has been observed in several cell
systems, but an understanding of its organelle-based physiological
activity remains incomplete. The purpose of the present study was to
investigate the mitochondrial 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 the signal peptide sequence
of murine Cox8l. Control cytosolic vectors (cEGFP,
c53DD) had the signal sequence placed in antisense orientation. NIH 3T3
cells were transiently transfected with these vectors in various
combinations. Mitochondrial 16S ribosomal RNA (16S rRNA) expression and
fluorochrome staining with Mitotracker Red CMXRos (
m) were
decreased in cells expressing m53DD. Both alterations were specific for
mitochondrial import competence (e.g., m53DD vs. c53DD) as well as the
passenger protein (e.g., m53DD vs. mEGFP). The normal functional state
of mitochondria was restored with PK11195, a specific ligand of the
mitochondrial peripheral-type benzodiazepine receptor. Negative
dominance of m53DD on 16S rRNA expression and CMXRos staining, and
rescue of these parameters with PK11195, imply a direct positive effect
of p53 on mitochondrial biogenesis and function.—Donahue, R. J.,
Razmara, M., Hoek, J. B., Knudsen, T. B. Direct influence of
the p53 tumor suppressor on mitochondrial biogenesis and function.
Key Words: 16S rRNA • PK11195 • peripheral benzodiazepine receptor
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