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


RESULTS
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.


CONCLUSIONS
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.
Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America. celine.douarre@umontreal.ca
Céline
C
Douarre
Carole
C
Sourbier
Ilaria
I
Dalla Rosa
Benu
B
Brata Das
Christophe E
CE
Redon
Hongliang
H
Zhang
Len
L
Neckers
Yves
Y
Pommier
D000818:Animals; D001343:Autophagy / Q000235:genetics; D004249:DNA Damage; D004264:DNA Topoisomerases, Type I / Q000235:genetics / Q000378:metabolism*; D004272:DNA, Mitochondrial; D004734:Energy Metabolism / Q000235:genetics; D005227:Fatty Acids / Q000378:metabolism; D006019:Glycolysis; D050155:Lipogenesis / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D015398:Signal Transduction
D004272:DNA, Mitochondrial; D005227:Fatty Acids; D004264:DNA Topoisomerases, Type I