Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8260240 | Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease | 2014 | 10 Pages |
Abstract
Long-chain 3-hydroxylated fatty acids (LCHFA) accumulate in long-chain 3-hydroxy-acyl-CoA dehydrogenase (LCHAD) and mitochondrial trifunctional protein (MTP) deficiencies. Affected patients usually present severe neonatal symptoms involving cardiac and hepatic functions, although long-term neurological abnormalities are also commonly observed. Since the underlying mechanisms of brain damage are practically unknown and have not been properly investigated, we studied the effects of LCHFA on important parameters of mitochondrial homeostasis in isolated mitochondria from cerebral cortex of developing rats. 3-Hydroxytetradecanoic acid (3 HTA) reduced mitochondrial membrane potential, NAD(P)H levels, Ca2Â + retention capacity and ATP content, besides inducing swelling, cytochrome c release and H2O2 production in Ca2Â +-loaded mitochondrial preparations. We also found that cyclosporine A plus ADP, as well as ruthenium red, a Ca2Â + uptake blocker, prevented these effects, suggesting the involvement of the mitochondrial permeability transition pore (mPTP) and an important role for Ca2Â +, respectively. 3-Hydroxydodecanoic and 3-hydroxypalmitic acids, that also accumulate in LCHAD and MTP deficiencies, similarly induced mitochondrial swelling and decreased ATP content, but to a variable degree pending on the size of their carbon chain. It is proposed that mPTP opening induced by LCHFA disrupts brain bioenergetics and may contribute at least partly to explain the neurologic dysfunction observed in patients affected by LCHAD and MTP deficiencies.
Keywords
N-[2-hydroxyethyl]piperazine-N′-[2-ethane-sulfonic acid]fluorescence arbitrary unitscarbonyl cyanide 3-chlorophenyl hydrazineFAUHEPESEGTALCHADALMLCFAantimycin AMTPMPTPCCCPAlamethicinBSAROSbovine serum albuminethylene glycol-bis(2-aminoethylether)-N,N,N′,N′-tetraacetic acidLong-chain fatty acidsPermeability transition poremitochondrial permeability transition poreCSAruthenium redblood brain barrierBBBcyclosporin AMitochondrial trifunctional proteinCalciumReactive oxygen species
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Authors
Anelise Miotti Tonin, Alexandre Umpierrez Amaral, Estela Natacha Busanello, Juciano Gasparotto, Daniel P. Gelain, Niels Gregersen, Moacir Wajner,