Disruption of oxidative phosphorylation and synaptic Na(+), K(+)-ATPase activity by pristanic acid in cerebellum of young rats.
[zellweger syndrome]
Peroxisomal biogenesis disorders (PBD) are inherited disorders clinically manifested by neurological symptoms and brain abnormalities, in which the cerebellum is usually involved. Biochemically, patients affected by these neurodegenerative diseases accumulate branched-chain fatty acids, including pristanic acid (Prist) in the brain and other tissues.In the present investigation we studied the in vitro influence of Prist, at doses found in PBD, on oxidative phosphorylation, by measuring the activities of the respiratory chain complexes I-IV and ATP production, as well as on creatine kinase and synaptic Na(+), K(+)-ATPase activities in rat cerebellum.Prist significantly decreased complexes I-III (65%), II (40%) and especially II-III (90%) activities, without altering the activities of complex IV of the respiratory chain and creatine kinase. Furthermore, ATP formation and synaptic Na(+), K(+)-ATPase activity were markedly inhibited (80-90%) by Prist. We also observed that this fatty acid altered mitochondrial and synaptic membrane fluidity that may have contributed to its inhibitory effects on the activities of the respiratory chain complexes and Na(+), K(+)-ATPase.Considering the importance of oxidative phosphorylation for mitochondrial homeostasis and of Na(+), K(+)-ATPase for the maintenance of cell membrane potential, the present data indicate that Prist compromises brain bioenergetics and neurotransmission in cerebellum. We postulate that these pathomechanisms may contribute to the cerebellar alterations observed in patients affected by PBD in which Prist is accumulated.
