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?

• Published in: Biochimica et biophysica acta 2014-09, Vol.1842 (9), p.1658-1667
• Main Authors: Tonin, Anelise Miotti, Amaral, Alexandre Umpierrez, Busanello, Estela Natacha, Gasparotto, Juciano, Gelain, Daniel P., Gregersen, Niels, Wajner, Moacir
• Format: Article
• Language: English
• Subjects: 3-Hydroxyacyl CoA Dehydrogenases - deficiency; 3-Hydroxyacyl CoA Dehydrogenases - metabolism; Acyl-CoA Dehydrogenase, Long-Chain - deficiency; Adenosine Triphosphate - metabolism; Animals; Brain energy homeostasis; Calcium; Calcium - metabolism; Cardiomyopathies - metabolism; Cardiomyopathies - pathology; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Cytochromes c - metabolism; Energy Metabolism - drug effects; Homeostasis; Hydrogen Peroxide - metabolism; Lauric Acids - pharmacology; Lipid Metabolism, Inborn Errors - metabolism; Lipid Metabolism, Inborn Errors - pathology; Long-chain 3-hydroxy acyl-CoA dehydrogenase deficiency; Membrane Potential, Mitochondrial - drug effects; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondrial Membrane Transport Proteins - drug effects; Mitochondrial Myopathies - metabolism; Mitochondrial Myopathies - pathology; Mitochondrial Swelling - drug effects; Mitochondrial Trifunctional Protein - metabolism; Mitochondrial trifunctional protein deficiency; Myristic Acids - pharmacology; NADP - metabolism; Nervous System Diseases - metabolism; Nervous System Diseases - pathology; Oxidants - metabolism; Palmitic Acids - pharmacology; Permeability transition pore; Rats; Rats, Wistar; Rhabdomyolysis - metabolism; Rhabdomyolysis - pathology
• ISSN: 0925-4439; 0006-3002; 1879-260X
• DOI: 10.1016/j.bbadis.2014.06.011

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, Ca2+ retention capacity and ATP content, besides inducing swelling, cytochrome c release and H2O2 production in Ca2+-loaded mitochondrial preparations. We also found that cyclosporine A plus ADP, as well as ruthenium red, a Ca2+ uptake blocker, prevented these effects, suggesting the involvement of the mitochondrial permeability transition pore (mPTP) and an important role for Ca2+, 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. •Long-chain 3-hydroxy fatty acids (LCHFA) are accumulated in LCHAD and MTP deficiencies.•Patients affected by these disorders present unexplained neurologic manifestations.•LCHFA induced mPTP opening in Ca2+-loaded mitochondria from rat cerebral cortex.•LCHFA plus Ca2+ disrupted mitochondrial energy homeostasis in rat cerebral cortex.