title: Experimental evidence that pristanic acid disrupts mitochondrial homeostasis in brain of young rats.
abstract: Patients affected by peroxisomal disorders commonly present neurologic dysfunction and brain abnormalities, whose neuropathology is poorly understood. Given that high sustained concentrations of pristanic acid (Prist) are found in the brain of these patients, it is conceivable that this complex branched-chain fatty acid is neurotoxic. Therefore, the present work investigated the in vitro effects of Prist at similar concentrations found in plasma of affected patients with some peroxisomal disorders on important parameters of energy homeostasis, including respiratory parameters determined by oxygen consumption, membrane potential (ΔΨm), NAD(P)H content, and swelling in mitochondrial preparations obtained from brain of young rats using glutamate plus malate or succinate as respiratory substrates. Prist markedly increased state 4 respiration and decreased state 3 respiration, the respiratory control ratio (RCR), and the ADP/O ratio with both substrates. The mitochondrial ΔΨm and the matrix NAD(P)H content were also decreased by Prist, which was also able to provoke mitochondrial swelling. Furthermore, Prist-induced mitochondrial swelling was dependent on oxidative damage to the permeability transition pore (PTP), because cyclosporine A and the thiol-reducing agent N-acetylcysteine totally prevented mitochondrial swelling. These data suggest that Prist impairs mitochondrial homeostasis, acting as an uncoupler of oxidative phosphorylation and as a metabolic inhibitor, besides causing mitochondrial swelling probably mediated by the permeability transition pore. It is proposed that these pathomechanisms may potentially be involved in the neurological abnormalities characteristic of the peroxisomal diseases in which Prist accumulates.
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Estela Natacha Brandt
authors.initials: EN
authors.lastname: Busanello
authors.forename: Alexandre Umpierrez
authors.initials: AU
authors.lastname: Amaral
authors.forename: Anelise Miotti
authors.initials: AM
authors.lastname: Tonin
authors.forename: Mateus
authors.initials: M
authors.lastname: Grings
authors.forename: Alana Pimentel
authors.initials: AP
authors.lastname: Moura
authors.forename: Paula
authors.initials: P
authors.lastname: Eichler
authors.forename: Carmen Regla
authors.initials: CR
authors.lastname: Vargas
authors.forename: Moacir
authors.initials: M
authors.lastname: Wajner
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D005227:Fatty Acids / Q000494:pharmacology*; D006706:Homeostasis / Q000187:drug effects*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D008933:Mitochondrial Swelling / Q000187:drug effects*; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
chemical_list: D005227:Fatty Acids; C002844:pristanic acid