Abstract
Increased levels of unconjugated bilirubin, the end product of heme catabolism, impair crucial aspects of nerve cell function. In previous studies, we demonstrated that bilirubin toxicity may be due to cell death by apoptosis. To characterize the sequence of events leading to neurotoxicity, we exposed developing rat brain astrocytes and neurons to unconjugated bilirubin and investigated whether changes in membrane dynamic properties can mediate apoptosis. Bilirubin induced a rapid, dose-dependent increase in apoptosis, which was nevertheless preceded by impaired mitochondrial metabolism. Using spin labels and electron paramagnetic resonance spectroscopy analysis of whole cell and isolated mitochondrial membranes exposed to bilirubin, we detected major membrane perturbation. By physically interacting with cell membranes, bilirubin induced an almost immediate increase in lipid polarity sensed at a superficial level. The enhanced membrane permeability coincided with an increase in lipid fluidity and protein mobility and was associated with significant oxidative injury to membrane lipids. In conclusion, apoptosis of nerve cells induced by bilirubin is mediated by its primary effect at physically perturbing the cell membrane. Bilirubin directly interacts with membranes influencing lipid polarity and fluidity, protein order, and redox status. These data suggest that nerve cell membranes are primary targets of bilirubin toxicity.
Highlights
Increased levels of unconjugated bilirubin, the end product of heme catabolism, impair crucial aspects of nerve cell function
We have recently shown that bilirubin induces cytochrome c release in developing rat brain neurons, in a process associated with caspase-3 activation and poly(ADP-ribose) polymerase (PARP) cleavage, requiring mitochondrial depolarization, together with Bax translocation [17]
The present study shows that apoptosis induced by bilirubin in nerve cells is rapid but preceded by disruption of mitochondrial metabolism
Summary
Increased levels of unconjugated bilirubin, the end product of heme catabolism, impair crucial aspects of nerve cell function. Bilirubin directly interacts with membranes influencing lipid polarity and fluidity, protein order, and redox status These data suggest that nerve cell membranes are primary targets of bilirubin toxicity.— Rodrigues, C. Bilirubin-induced apoptosis may occur via activation of N-methyl-daspartate (NMDA) receptors, as it has been described in vivo using the Gunn rat model [18] and recently confirmed in vitro using rat brain neurons [14] These cellular manifestations of bilirubin toxicity have been ascribed, in part, to its affinity for membrane lipids [19,20,21,22], changing membrane lipid composition [23] and modifying lipid order in erythrocytes [24] and mitochondria [25].
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