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PLoS One. 2012;7(7):e41094. doi: 10.1371/journal.pone.0041094. Epub 2012 Jul 20.

Mitochondrial topoisomerase I is critical for mitochondrial integrity and cellular energy metabolism.

Author information

1
Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America. celine.douarre@umontreal.ca

Abstract

BACKGROUND:

Mitochondria contain their own DNA genome (mtDNA), as well as specific DNA replication and protein synthesis machineries. Relaxation of the circular, double-stranded mtDNA relies on the presence of topoisomerase activity. Three different topoisomerases have been identified in mitochondria: Top1mt, Top3α and a truncated form of Top2β.

METHODOLOGY/PRINCIPAL FINDINGS:

The present study shows the importance of Top1mt in mitochondrial homeostasis. Here we show that Top1mt-/- murine embryonic fibroblasts (MEF) exhibit dysfunctional mitochondrial respiration, which leads decreased ATP production and compensation by increased glycolysis and fatty acid oxidation. ROS production in Top1mt-/- MEF cells is involved in nuclear DNA damage and induction of autophagy. Lack of Top1mt also triggers oxidative stress and DNA damage associated with lipid peroxidation and mitophagy in Top1mt-/- mice.

CONCLUSION/SIGNIFICANCE:

Together, our data implicate Top1mt for mitochondrial integrity and energy metabolism. The compensation mechanism described here contributes to the survival of Top1mt-/- cells and mice despite alterations of mitochondrial functions and metabolism. Therefore, this study supports a novel model for cellular adaptation to mitochondrial damage.

PMID:
22911747
PMCID:
PMC3401127
DOI:
10.1371/journal.pone.0041094
[Indexed for MEDLINE]
Free PMC Article

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