Disruption of mitochondrial homeostasis by phytanic acid in cerebellum of young rats.
Phytanic acid (Phyt) brain concentrations are highly increased in Refsum disease, a peroxisomal disorder clinically characterized by neurological features, cardiac abnormalities, and retinitis pigmentosa. Considering that the pathogenesis of cerebellar ataxia, a common finding in this disease, is still unknown, in the present work we investigated the in vitro effects of Phyt at concentrations similar to those found in affected patients on important parameters of mitochondrial homeostasis in cerebellum from young rats. The respiratory parameters states 3 and 4 and respiratory control ratio (RCR) determined by oxygen consumption, membrane potential (∆Ψm), NAD(P)H pool content, and swelling were evaluated in mitochondrial preparations from this cerebral structure. Phyt markedly increased state 4 respiration, whereas state 3 respiration, the RCR, the mitochondrial matrix NAD(P)H content, and ∆Ψm were decreased by this fatty acid, being the latter effect partially prevented by N-acetylcysteine. These data indicate that Phyt behaves as an uncoupler of oxidative phosphorylation and as a metabolic inhibitor disrupting mitochondrial homeostasis in cerebellum. It is proposed that these pathomechanisms may contribute at least in part to the cerebellar alterations found in Refsum disease.
Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, Porto Alegre, RS, Brazil.
Estela Natacha Brandt
EN
Busanello
Alexandre Umpierrez
AU
Amaral
Anelise Miotti
AM
Tonin
Angela
A
Zanatta
Carolina Maso
CM
Viegas
Carmen Regla
CR
Vargas
Moacir
M
Wajner
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D002531:Cerebellum / Q000648:ultrastructure*; D004305:Dose-Response Relationship, Drug; D018698:Glutamic Acid / Q000494:pharmacology; D006706:Homeostasis / Q000187:drug effects*; D007656:Ketoglutaric Acids / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000473:pathology; D009249:NADP / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D010831:Phytanic Acid / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018709:Statistics, Nonparametric
D007656:Ketoglutaric Acids; D010831:Phytanic Acid; D018698:Glutamic Acid; D009249:NADP; D000244:Adenosine Diphosphate