Mitochondrial reactive oxygen species trigger hypoxia-inducible factor-dependent extension of the replicative life span during hypoxia.
Physiological hypoxia extends the replicative life span of human cells in culture. Here, we report that hypoxic extension of replicative life span is associated with an increase in mitochondrial reactive oxygen species (ROS) in primary human lung fibroblasts. The generation of mitochondrial ROS is necessary for hypoxic activation of the transcription factor hypoxia-inducible factor (HIF). The hypoxic extension of replicative life span is ablated by a dominant negative HIF. HIF is sufficient to induce telomerase reverse transcriptase mRNA and telomerase activity and to extend replicative life span. Furthermore, the down-regulation of the von Hippel-Lindau tumor suppressor protein by RNA interference increases HIF activity and extends replicative life span under normoxia. These findings provide genetic evidence that hypoxia utilizes mitochondrial ROS as signaling molecules to activate HIF-dependent extension of replicative life span.
Bell
Eric L
EL
The Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
Klimova
Tatyana A
TA
Eisenbart
James
J
Schumacker
Paul T
PT
Chandel
Navdeep S
NS
D015687:Cell Hypoxia / Q000187:drug effects; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects; D003600:Cytosol / Q000187:drug effects; D004249:DNA Damage; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D010100:Oxygen / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D019098:Telomerase / Q000235:genetics; D013816:Thermodynamics; D014158:Transcription, Genetic / Q000187:drug effects; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism
D051793:Hypoxia-Inducible Factor 1; D017382:Reactive Oxygen Species; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D019098:Telomerase; D010100:Oxygen