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

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 demons...

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Vydané v:Biochimica et biophysica acta Ročník 1787; číslo 5; s. 328 - 334
Hlavní autori: Lebedeva, Maria A., Eaton, Jana S., Shadel, Gerald S.
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: Netherlands Elsevier B.V 01.05.2009
Predmet:
Animals
Cancer
DNA Primers
DNA, Mitochondrial - genetics
Fibroblasts - cytology
Fibroblasts - physiology
Gene Deletion
Homeostasis
Humans
Membrane Potentials
Mice
Mice, Inbred C57BL
Mice, Knockout
Mitochondria - metabolism
Mitochondria - physiology
Mitochondrial transcription factor A
mtDNA depletion
Oxidative Phosphorylation
p53
p53R2
Polymerase Chain Reaction
Reactive oxygen species
Reactive Oxygen Species - metabolism
RNA, Messenger - genetics
Transcription, Genetic
Tumor Suppressor Protein p53 - deficiency
Tumor Suppressor Protein p53 - genetics
Mitochondrial transcription factor A
Reactive oxygen species
mtDNA depletion
p53R2
p53
Cancer
ISSN:0005-2728, 0006-3002, 1879-2650
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Shrnutí: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.
Bibliografia:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0005-2728
0006-3002
1879-2650
DOI:10.1016/j.bbabio.2009.01.004