The plasma membrane redox system (PMRS) containing
NADH-dependent
reductases is known to be involved in the maintenance of redox state and bioenergetics. Neuronal cells are very vulnerable to oxidative stress and altered energy metabolism linked to
mitochondrial dysfunction. However, the role of the PMRS in these pathways is far from clear. In this study, in order to investigate how
cytochrome b5 reductase (b5R), one of the PM redox
enzymes, regulates cellular response under stressed conditions, human
neuroblastoma cells transfected with b5R were used for viability and mitochondrial functional assays. Cells transfected with b5R exhibited significantly higher levels of the
NAD(+)/
NADH ratio, consistent with increased levels of b5R activity. Overexpression of b5R made cells more resistant to H2O2 (oxidative stress),
2-deoxyglucose (metabolic stress),
rotenone and
antimycin A (energetic stress), and
lactacystin (proteotoxic stress), but did not protect cells against H2O2 and serum withdrawal. Overexpression of b5R induced higher mitochondrial functions such as
ATP production rate, oxygen consumption rate, and activities of complexes I and II, without formation of further
reactive oxygen species, consistent with lower levels of oxidative/nitrative damage and resistance to apoptotic cell death. In conclusion, higher
NAD(+)/
NADH ratio and consequent more efficient mitochondrial functions are induced by the PMRS, enabling them to maintain redox state and energy metabolism under conditions of some energetic stresses. This suggests that b5R can be a target for therapeutic intervention for aging and
neurodegenerative diseases.