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PMID: 19413947 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Loss of p53 causes mitochondrial DNA depletion and altered mitochondrial reactive oxygen species homeostasis.

Biochimica et biophysica acta ·Vol. 1787 ·No. 5 ·2009-05-00 ·Pages 328-34

Lebedeva MA, Eaton JS, Shadel GS

Abstract

In addition to its central role in cellular stress signaling, the tumor suppressor p53 modulates mitochondrial respiration through its nuclear transcription factor activity and localizes to mitochondria, where it enhances apoptosis and suppresses mitochondrial DNA (mtDNA) mutagenesis. Here we demonstrate a new conserved role for p53 in mtDNA copy number maintenance and mitochondrial reactive oxygen species (ROS) homeostasis. In mammals, mtDNA is present at thousands of copies per cell and is essential for normal development and cell function. We show that p53 null mouse and p53 knockdown human primary fibroblasts exhibit mtDNA depletion and decreased mitochondrial mass under normal culture growth conditions. This is accompanied by a reduction of the p53R2 subunit of ribonucleotide reductase mRNA and protein and of mitochondrial transcription factor A (mtTFA) at the protein level only. Finally, p53-depleted cells exhibit significant disruption of cellular ROS homeostasis, characterized by reduced mitochondrial and cellular superoxide levels and increased cellular hydrogen peroxide. Altogether, these results elucidate additional mitochondria-related functions for p53 and implicate mtDNA depletion and ROS alterations as potentially relevant to cellular transformation, cancer cell phenotypes, and the Warburg Effect.

MeSH Terms
Animals DNA Primers DNA, Mitochondrial/genetics Fibroblasts/cytology,physiology Gene Deletion Homeostasis Humans Membrane Potentials Mice Mice, Inbred C57BL Mice, Knockout Mitochondria/metabolism,physiology Oxidative Phosphorylation Polymerase Chain Reaction RNA, Messenger/genetics Reactive Oxygen Species/metabolism Transcription, Genetic Tumor Suppressor Protein p53/deficiency,genetics
Chemicals
DNA Primers DNA, Mitochondrial RNA, Messenger Reactive Oxygen Species Tumor Suppressor Protein p53
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Lebedeva Maria A
Department of Pathology, Yale University School of Medicine, New Haven, CT 06520-8023, USA.
Eaton Jana S
Shadel Gerald S
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Article Info
Journal
Biochimica et biophysica acta
Abbr.
Biochim Biophys Acta
ISSN
0006-3002
DOI
10.1016/j.bbabio.2009.01.004
Published
2009-05-00
Epub
2009-00-20
Pages
328-34
Language
English
Region
Netherlands
NLM ID
0217513
PMCID
PMC2680458
Subset
IM
Grants
NIGMS NIH HHS · T32 GM007223 · United States
NINDS NIH HHS · R01 NS056206-02 · United States
NINDS NIH HHS · NS056206 · United States
NIGMS NIH HHS · T32GM007223 · United States
NINDS NIH HHS · R01 NS056206 · United States
External Links
PubMed source DOI: 10.1016/j.bbabio.2009.01.004 PMC Full Text
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