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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Uncoupling, metabolic inhibition and induction of mitochondrial permeability transition in rat liver mitochondria caused by the major long-chain hydroxyl monocarboxylic fatty acids accumulating in LCHAD deficiency

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Hickmann, Fernanda Hermes [1] ; Cecatto, Cristiane [1] ; Kleemann, Daniele [1] ; Monteiro, Wagner Oliveira [1] ; Castilho, Roger Frigerio [2] ; Amaral, Alexandre Umpierrez [1] ; Wajner, Moacir [1, 3]
Total Authors: 7
[1] Univ Fed Rio Grande do Sul, Inst Ciencias Basicas Saude, Dept Bioquim, BR-90035003 Porto Alegre, RS - Brazil
[2] Univ Estadual Campinas, Fac Ciencias Med, Dept Patol Clin, Campinas, SP - Brazil
[3] Hosp Clin Porto Alegre, Serv Genet Med, Porto Alegre, RS - Brazil
Total Affiliations: 3
Document type: Journal article
Source: BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS; v. 1847, n. 6-7, p. 620-628, JUN-JUL 2015.
Web of Science Citations: 8

Patients with long-chain 3-hydroxy-acyl-CoA dehydrogenase (LCHAD) deficiency commonly present liver dysfunction whose pathogenesis is unknown. We studied the effects of long-chain 3-hydroxylated fatty acids (LCHFA) that accumulate in LCHAD deficiency on liver bioenergetics using mitochondrial preparations from young rats. We provide strong evidence that 3-hydroxytetradecanoic (3HTA) and 3-hydroxypalmitic (3HPA) acids, the monocarboxylic acids that are found at the highest tissue concentrations in this disorder, act as metabolic inhibitors and uncouplers of oxidative phosphorylation. These conclusions are based on the findings that these fatty acids decreased ADP-stimulated (state 3) and uncoupled respiration, mitochondrial membrane potential and NAD(P)H content, and, in contrast, increased resting (state 4) respiration. We also verified that 3HTA and 3HPA markedly reduced Ca2+ retention capacity and induced swelling in Ca2+-loaded mitochondria. These effects were mediated by mitochondrial permeability transition (MPT) induction since they were totally prevented by the classical MPT inhibitors cyclosporin A and ADP, as well as by ruthenium red, a Ca2+ uptake blocker. Taken together, our data demonstrate that the major monocarboxylic LCHFA accumulating in LCHAD deficiency disrupt energy mitochondrial homeostasis in the liver. It is proposed that this pathomechanism may explain at least in part the hepatic alterations characteristic of the affected patients. (C) 2015 Elsevier B.V. All rights reserved. (AU)

FAPESP's process: 11/50400-0 - Mitochondrial energy metabolism, redox state and functionality in cell death and cardiometabolic and neurodegenerative disorders
Grantee:Aníbal Eugênio Vercesi
Support type: Research Projects - Thematic Grants