NDLI: Ethylmalonic Acid Induces Permeability Transition in Isolated Brain Mitochondria

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Ethylmalonic Acid Induces Permeability Transition in Isolated Brain Mitochondria

Content Provider	Springer Nature Link
Author	Cecatto, Cristiane Amaral, Alexandre Umpierrez Leipnitz, Guilhian Castilho, Roger Frigério Wajner, Moacir
Copyright Year	2014
Abstract	Predominant accumulation of ethylmalonic acid (EMA) in tissues and biological fluids is a characteristic of patients affected by short chain acyl-CoA dehydrogenase deficiency and ethylmalonic encephalopathy. Neurological abnormalities are frequently found in these disorders, but the mechanisms underlying the brain injury are still obscure. Since hyperlacticacidemia is also found in many affected patients indicating a mitochondrial dysfunction; in the present work, we evaluated the in vitro and ex vivo effects of EMA plus Ca$^{2+}$ on mitochondrial integrity and redox balance in succinate-supported brain organelles. We verified that the evaluated parameters were disturbed only when EMA was associated with exogenous micromolar Ca$^{2+}$ concentrations. Thus, we found that this short chain organic acid plus Ca$^{2+}$ dissipated the membrane potential and provoked mitochondrial swelling, as well as impaired the mitochondrial Ca$^{2+}$ retention capacity, resulting in a rapid Ca$^{2+}$ release and decreased NAD(P)H matrix content. In contrast, EMA was not able to stimulate mitochondrial hydrogen peroxide generation. We also observed that all these effects were prevented by the mitochondrial Ca$^{2+}$ uptake inhibitor ruthenium red and the mitochondrial permeability transition (MPT) inhibitors cyclosporin A (CsA) and ADP. Furthermore, mitochondria isolated from rat brains after in vivo intrastriatal administration of EMA was more susceptible to Ca$^{2+}$-induced swelling, which was fully prevented by CsA and ADP. Finally, EMA significantly decreased striatal slice viability, which was attenuated by CsA. The data strongly indicate that EMA reduced the mitochondrial threshold for Ca$^{2+}$-induced MPT reinforcing the role of this cation in EMA-induced disruption of mitochondrial bioenergetics. It is, therefore, presumed that EMA acting synergistically with Ca$^{2+}$ compromises mitochondrial energy homeostasis in the central nervous system that may explain at least in part the neurologic alterations presented by patients with abnormal levels of this organic acid.
Starting Page	168
Ending Page	178
Page Count	11
File Format	PDF
ISSN	10298428
Journal	Neurotoxicity Research
Volume Number	26
Issue Number	2
e-ISSN	14763524
Language	English
Publisher	Springer US
Publisher Date	2014-02-21
Publisher Place	Boston
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Short chain acyl-CoA dehydrogenase deficiency Ethylmalonic encephalopathy Mitochondrial integrity Redox balance Calcium Neurosciences Neurology Neurochemistry Pharmacology/Toxicology Neurobiology Cell Biology
Content Type	Text
Resource Type	Article
Subject	Neuroscience Toxicology

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Ethylmalonic Acid Induces Permeability Transition in Isolated Brain Mitochondria