Abstract 2620: C1q Exacerbates Mitochondrial Dysfunction Without Activation Of The Terminal Complement In Neonatal Mice With Hypoxic-ischemic Brain Injury.
Deletion of C1q protects developing brain against hypoxia-ischemia (HI) (Ten V et al; 2005).
Hypothesis. C1q mediates HI-brain injury by:
Activation of terminal complement or/and
Exacerbation of mitochondrial dysfunction.
Hypothesis (1) P7 WT (C57Bl/6j) pre-treated with vehicle or sCD59; progenies of C1q+/-, Factor B/C2-/-/-/- inter-mating were subjected to HI: ligation of right carotid artery + hypoxic exposure. At 24 hr of reperfusion the extent of damage, cerebral deposition of C1q, C3, iC3b and C9 were assessed. Hypothesis (2) In C1q-/-and WT mice cerebral ATP-content, mitochondrial O2-consumption rate, H2O2-production and membrane potential (î»m) were studied immediately after HI. At 12 hr electron microscopy for co-staining of C1q and gC1qR/p33 in neurons was performed. WT and C1q-/- cortical and granule neurons in culture were subjected to glutamate or energy failure stress (EFS), glucose deprivation and exposure to 5 mM Na azide. At 24 hr after stress cellular viability, C1q protein and C9 mRNA expression were examined.
Results. C1q-/- mice were significantly protected against HI compared to +/+ counterparts. This was associated with robust attenuation of deposition of C3, iC3b and C9 in brain. However, no protection was detected in FB/C2-/ -/ -/ - and sCD59-pretreated mice, although C9-deposition in the injured brain was significantly decreased compared to controls. C1q-/ - mice exhibited a stunning preservation of ATP in the ischemic brain immediately after HI. This was associated with higher O2-consumption rate in state 3 and significantly (two-folds) less production of H2O2 by C1q-/ - mitochondria compared to WT-counterparts without difference in the î»m. In WT-mice HI resulted in intraneuronal, and intramitochondrial accumulation of C1q and gC1qR/p33 only in the ischemic hemisphere. C1q-/ - vs WT cultured neurons were significantly protected against excitotoxic and EFS in the absence of C9-mRNA in cellular lysate.
Conclusion. C1q mediates HI-injury. Terminal complement activation has no role in C1q-mediated neuronal damage. The presence of C1q is associated with significantly increased mitochondrial ROS-production in HI-brain. This may represent a novel mechanism for HI-neurodegeneration.