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Biochim Biophys Acta. 2014 Sep;1842(9):1658-67. doi: 10.1016/j.bbadis.2014.06.011. Epub 2014 Jun 16.

Mitochondrial bioenergetics deregulation caused by long-chain 3-hydroxy fatty acids accumulating in LCHAD and MTP deficiencies in rat brain: a possible role of mPTP opening as a pathomechanism in these disorders?

Author information

1
Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Research Unit for Molecular Medicine, Aarhus University Hospital, Department of Clinical Medicine, Aarhus University, 8200 Aarhus, Denmark.
2
Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
3
Research Unit for Molecular Medicine, Aarhus University Hospital, Department of Clinical Medicine, Aarhus University, 8200 Aarhus, Denmark.
4
Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, RS, Brazil. Electronic address: mwajner@ufrgs.br.

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, Ca(2+) retention capacity and ATP content, besides inducing swelling, cytochrome c release and H2O2 production in Ca(2+)-loaded mitochondrial preparations. We also found that cyclosporine A plus ADP, as well as ruthenium red, a Ca(2+) uptake blocker, prevented these effects, suggesting the involvement of the mitochondrial permeability transition pore (mPTP) and an important role for Ca(2+), 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:

Brain energy homeostasis; Calcium; Long-chain 3-hydroxy acyl-CoA dehydrogenase deficiency; Mitochondrial trifunctional protein deficiency; Permeability transition pore

PMID:
24946182
DOI:
10.1016/j.bbadis.2014.06.011
[Indexed for MEDLINE]
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