title: UCP2 and ANT differently modulate proton-leak in brain mitochondria of long-term hyperglycemic and recurrent hypoglycemic rats.
abstract: A growing body of evidence suggests that mitochondrial proton-leak functions as a regulator of reactive oxygen species production and its modulation may limit oxidative injury to tissues. The main purpose of this work was to characterize the proton-leak of brain cortical mitochondria from long-term hyperglycemic and insulin-induced recurrent hypoglycemic rats through the modulation of the uncoupling protein 2 (UCP2) and adenine nucleotide translocator (ANT). Streptozotocin-induced diabetic rats were treated subcutaneously with twice-daily insulin injections during 2 weeks to induce the hypoglycemic episodes. No differences in the basal proton-leak, UCP2 and ANT protein levels were observed between the experimental groups. Mitochondria from recurrent hypoglycemic rats presented a decrease in proton-leak in the presence of GDP, a specific UCP2 inhibitor, while an increase in proton-leak was observed in the presence of linoleic acid, a proton-leak activator, this effect being reverted by the simultaneous addition of GDP. Mitochondria from long-term hyperglycemic rats showed an enhanced susceptibility to ANT modulation as demonstrated by the complete inhibition of basal and linoleic acid-induced proton-leak caused by the ANT specific inhibitor carboxyatractyloside. Our results show that recurrent-hypoglycemia renders mitochondria more susceptible to UCPs modulation while the proton-leak of long-term hyperglycemic rats is mainly modulated by ANT, which suggest that brain cortical mitochondria have distinct adaptation mechanisms in face of different metabolic insults.
authors.affiliation: Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517, Coimbra, Portugal.
authors.forename: Susana
authors.initials: S
authors.lastname: Cardoso
authors.forename: Maria S
authors.initials: MS
authors.lastname: Santos
authors.forename: António
authors.initials: A
authors.lastname: Moreno
authors.forename: Paula I
authors.initials: PI
authors.lastname: Moreira
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D004195:Disease Models, Animal; D006943:Hyperglycemia / Q000378:metabolism; D007003:Hypoglycemia / Q000378:metabolism; D007473:Ion Channels / Q000378:metabolism*; D019787:Linoleic Acid / Q000494:pharmacology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D000226:Mitochondrial ADP, ATP Translocases / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D000071246:Uncoupling Protein 2
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; C000604391:Ucp2 protein, rat; D000071246:Uncoupling Protein 2; D000226:Mitochondrial ADP, ATP Translocases; D019787:Linoleic Acid