Mitochondria as the target for mildronate's protective effects in azidothymidine (AZT)-induced toxicity of isolated rat liver mitochondria.
Previously mildronate, an aza-butyrobetaine derivative, was shown to be a cytoprotective drug, through its mechanism of action of inhibition of carnitine palmitoyltransferase-1, thus protecting mitochondria from long-chain fatty acid accumulation and subsequent damage. Recently in an azidothymidine (AZT)-induced cardiotoxicity model in vivo (in mice), we have found mildronate's ability of protecting heart tissue from nuclear factor kappaB abnormal expression. Preliminary data also demonstrate cerebro- and hepatoprotecting properties of mildronate in AZT-toxicity models. We suggest that mildronate may target its action predominantly to mitochondria. The present study in isolated rat liver mitochondria was designed to clarify mitochondrial targets for mildronate by using AZT as a model compound. The aim of this study was to investigate: (1) whether mildronate may protect mitochondria from AZT-induced toxicity; and (2) which is the most critical target in mitochondrial processes that is responsible for mildronate's regulatory action. The results showed that mildronate protected mitochondria from AZT-induced damage predominantly at the level of complex I, mainly by reducing hydrogen peroxide generation. Significant protection of AZT-caused inhibition of uncoupled respiration, ADP to oxygen ratio, and transmembrane potential were also observed. Mildronate per se had no effect on the bioenergetics, oxidative stress, or permeability transition of rat liver mitochondria. Since mitochondrial complex I is the first enzyme of the respiratory electron transport chain and its damage is considered to be responsible for different mitochondrial diseases, we may account for mildronate's effectiveness in the prevention of pathologies associated with mitochondrial dysfunctions.
Pupure
Jolanta
J
Department of Pharmacology, Faculty of Medicine, University of Latvia, Riga, Latvia. pupure@e-apollo.lv
Fernandes
Maria A S
MA
Santos
Maria S
MS
Moreno
António J M
AJ
Kalvinsh
Ivars
I
Klusa
Vija
V
Oliveira
Catarina R
CR
D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology*; D019069:Cell Respiration / Q000187:drug effects; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D004734:Energy Metabolism / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008763:Methylhydrazines / Q000494:pharmacology*; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000473:pathology; D028361:Mitochondrial Diseases / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D015215:Zidovudine / Q000037:antagonists & inhibitors* / Q000633:toxicity*
D000963:Antimetabolites; D008763:Methylhydrazines; D015215:Zidovudine; C050147:3-(2,2,2-trimethylhydrazine)propionate