Mitochondrial respiration protects against oxygen-associated DNA damage.
Oxygen is not only required for oxidative phosphorylation but also serves as the essential substrate for the formation of reactive oxygen species (ROS), which is implicated in ageing and tumorigenesis. Although the mitochondrion is known for its bioenergetic function, the symbiotic theory originally proposed that it provided protection against the toxicity of increasing oxygen in the primordial atmosphere. Using human cells lacking Synthesis of Cytochrome c Oxidase 2 (SCO2-/-), we have tested the oxygen toxicity hypothesis. These cells are oxidative phosphorylation defective and glycolysis dependent; they exhibit increased viability under hypoxia and feature an inverted growth response to oxygen compared with wild-type cells. SCO2-/- cells have increased intracellular oxygen and nicotinamide adenine dinucleotide (NADH) levels, which result in increased ROS and oxidative DNA damage. Using this isogenic cell line, we have revealed the genotoxicity of ambient oxygen. Our study highlights the importance of mitochondrial respiration both for bioenergetic benefits and for maintaining genomic stability in an oxygen-rich environment.
Sung
Ho Joong
HJ
Translational Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Ma
Wenzhe
W
Wang
Ping-yuan
PY
Hynes
James
J
O'Riordan
Tomas C
TC
Combs
Christian A
CA
McCoy
J Philip
JP
Bunz
Fred
F
Kang
Ju-gyeong
JG
Hwang
Paul M
PM
D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D019069:Cell Respiration / Q000235:genetics / Q000502:physiology*; D004249:DNA Damage / Q000235:genetics / Q000502:physiology; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D045325:HCT116 Cells; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D018832:Molecular Chaperones; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology; D010100:Oxygen / Q000378:metabolism*; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism
D002352:Carrier Proteins; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones; D017382:Reactive Oxygen Species; C400285:SCO2 protein, human; D010100:Oxygen