Downregulation of mitochondrial telomerase reverse transcriptase induced by H2O2 is Src kinase dependent.
Telomerase with its catalytic subunit telomerase reverse transcriptase (TERT) prevents telomere erosion in the nucleus. In addition, telomerase has also telomere-independent functions in protection from apoptosis. Unexpectedly, TERT was found in the mitochondria. However, its regulation in this organelle is completely unknown. Here, we demonstrate that mitochondrial TERT is downregulated by exposure to H(2)O(2) in primary human endothelial cells. This depletion is dependent on the Src phosphorylation site within TERT, tyrosine 707. In accordance with this finding, we also detected Src in the mitochondria and demonstrated that Src is activated upon H(2)O(2) treatment. This regulation of mitochondrial TERT is reminiscent of the situation in the nucleus from where TERT is exported under conditions of oxidative stress in a Src kinase dependent manner. In addition, Akt1 was also found in the mitochondria and H(2)O(2) treatment led to reduced active Akt1 in these organelles, suggesting that similar regulatory mechanisms operate in mitochondria and the nucleus.
Büchner
Nicole
N
Associated Leibniz-Institute for Preventive Medicine , University of Duesseldorf gGmbH, Duesseldorf, Germany.
Zschauer
Tim-Christian
TC
Lukosz
Margarete
M
Altschmied
Joachim
J
Haendeler
Judith
J
D001483:Base Sequence; D001665:Binding Sites; D002467:Cell Nucleus / Q000201:enzymology; D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D018384:Oxidative Stress; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019098:Telomerase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014443:Tyrosine / Q000737:chemistry; D019061:src-Family Kinases / Q000378:metabolism*
D017931:DNA Primers; D014443:Tyrosine; D006861:Hydrogen Peroxide; D019061:src-Family Kinases; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; C509186:TERT protein, human; D019098:Telomerase