Mitochondrial Topoisomerase I is Critical for Mitochondrial Integrity and Cellular Energy Metabolism

作者：Douarre Celine^*; Sourbier Carole; Dalla Rosa Ilaria; Das Benu Brata; Redon Christophe E; Zhang Hongliang; Neckers Len; Pommier Yves

来源：PLos One, 2012, 7(7): e41094.

DOI：10.1371/journal.pone.0041094

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, Top3 alpha and a truncated form of Top2 beta.
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.

• 出版日期2012-7-20