The nuclear factor kappa B (NF-κB) signaling pathway is involved in ammonia-induced mitochondrial dysfunction

Hyperammonemia is very toxic to the brain, leading to inflammation, disruption of brain cellular energy metabolism and cognitive function. However, the underlying mechanism(s) for these impairments is still not fully understood. This study investigated the effects of ammonia in hippocampal astroglia derived from C57BL/6 mice. Parameters measured included oxygen consumption rates (OCR), ATP, cytochrome c oxidase (COX) activity, alterations in oxidative phosphorylation (OXPHOS), nuclear factor kappa B (NF-kappa B) subunits, key regulators of mitochondrial biogenesis (peroxisome proliferator-activated receptor gamma coactivator1-alpha (PGC1 alpha), calcium/calmodulin-dependent protein kinase II (CaMKII), cAMP-response element binding protein (CREB), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), early growth response (Egr) factor family of proteins, and mitochondrial transcription factor A (TFAM). Ammonia was found to decrease mitochondrial numbers, potentially through a CaMKII-CREB-PGC1 alpha-Nrf2 pathway in astroglia. Ammonia did not alter the levels of Egrs and TFAM in astroglia. Ammonia decreased OCR, ATP, COX, and OXPHOS levels in astroglia. To assess whether energy metabolism is reduced by ammonia through NF-kappa B associated pathways, astroglia were treated with ammonia alone or with NF-kappa B inhibitors such as Bay11-7082 or SN50. Mitochondrial OCR levels were reduced in the presence of NF-kappa B inhibitors; however co-treatment of NF-kappa B inhibitors and ammonia reversed mitochondrial deficits. Further, ammonia increased translocation of the NF-kappa B p65 into the nucleus of astroglia that correlates with an increased activity of NF-kappa B. These findings suggest that the NF-kappa B signaling pathway is putatively involved in ammonia-induced changes in bioenergetics in astroglia. Such research has critical implications for the treatment of disorders in which brain bioenergetics is compromised.

Automated summary

This study found that ammonia decreased mitochondrial numbers in astroglia through a CaMKII-CREB-PGC1α-Nrf2 pathway, leading to reduced OCR, ATP, COX, and OXPHOS levels. Treatment with NF-kappa B inhibitors reversed the mitochondrial deficits induced by ammonia, suggesting the involvement of the NF-kappa B signaling pathway in ammonia-induced changes in bioenergetics in astroglia.