Complement component c1q mediates mitochondria-driven oxidative stress in neonatal hypoxic-ischemic brain injury.
Hypoxic-ischemic (HI) brain injury in infants is a leading cause of lifelong disability. We report a novel pathway mediating oxidative brain injury after hypoxia-ischemia in which C1q plays a central role. Neonatal mice incapable of classical or terminal complement activation because of C1q or C6 deficiency or pharmacologically inhibited assembly of membrane attack complex were subjected to hypoxia-ischemia. Only C1q(-/-) mice exhibited neuroprotection coupled with attenuated oxidative brain injury. This was associated with reduced production of reactive oxygen species (ROS) in C1q(-/-) brain mitochondria and preserved activity of the respiratory chain. Compared with C1q(+/+) neurons, cortical C1q(-/-) neurons exhibited resistance to oxygen-glucose deprivation. However, postischemic exposure to exogenous C1q increased both mitochondrial ROS production and mortality of C1q(-/-) neurons. This C1q toxicity was abolished by coexposure to antioxidant Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid). Thus, the C1q component of complement, accelerating mitochondrial ROS emission, exacerbates oxidative injury in the developing HI brain. The terminal complement complex is activated in the HI neonatal brain but appeared to be nonpathogenic. These findings have important implications for design of the proper therapeutic interventions against HI neonatal brain injury by highlighting a pathogenic priority of C1q-mediated mitochondrial oxidative stress over the C1q deposition-triggered terminal complement activation.
Ten
Vadim S
VS
Departments of Pediatrics, Neurosurgery, and Physiology and Cellular Biophysics, Columbia University, New York, New York 10032, USA. vt82@columbia.edu
Yao
Jun
J
Ratner
Veniamin
V
Sosunov
Sergey
S
Fraser
Deborah A
DA
Botto
Marina
M
Sivasankar
Baalasubramanian
B
Morgan
B Paul
BP
Silverstein
Samuel
S
Stark
Raymond
R
Polin
Richard
R
Vannucci
Susan J
SJ
Pinsky
David
D
Starkov
Anatoly A
AA
D000818:Animals; D000831:Animals, Newborn; D020520:Brain Infarction / Q000378:metabolism / Q000473:pathology; D018957:CD59 Antigens / Q000494:pharmacology; D002478:Cells, Cultured; D003167:Complement Activation; D015922:Complement C1q / Q000235:genetics / Q000502:physiology*; D003600:Cytosol / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000172:deficiency; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000502:physiology*; D009474:Neurons / Q000378:metabolism; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
D018957:CD59 Antigens; D017382:Reactive Oxygen Species; D015922:Complement C1q; D005947:Glucose; D010100:Oxygen