cis-4-decenoic acid provokes mitochondrial bioenergetic dysfunction in rat brain

Schuck, Patrícia Fernanda; Ferreira, Gustavo da Costa; Tahara, Erich Birelli; Klamt, Fábio; Kowaltowski, Alicia J.; Wajner, Moaçir

doi:10.1016/j.lfs.2010.05.019

Cited by 11 publications

(6 citation statements)

References 48 publications

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“…It is postulated that clinical symptoms, including CNS complications such as convulsion, coma and lethargy, may be triggered by the accumulation of metabolites and their acyl-CoA derivatives that disrupt intermediary metabolism [66–69]. The hydrolysis of the acyl-CoA derivatives and subsequent accumulation of free organic acids can lead to severe acidosis that can be life threatening [3].…”

Section: Neuroprotection Afforded By L-carnitine Supplementation In Pmentioning

confidence: 99%

l-Carnitine and Acetyl-l-carnitine Roles and Neuroprotection in Developing Brain

2017

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L-Carnitine functions to transport long chain fatty acyl CoAs into the mitochondria for degradation by β-oxidation. Treatment with L-carnitine can ameliorate metabolic imbalance in many inborn errors of metabolism. In recent years there has been considerable interest in the therapeutic potential of L-carnitine and its acetylated derivative acetyl-L-carnitine (ALCAR) for neuroprotection in a number of disorders including hypoxia-ischemia, traumatic brain injury, Alzheimer’s disease and in conditions leading to central or peripheral nervous system injury. There is compelling evidence from preclinical studies that L-carnitine and ALCAR can improve energy status, decrease oxidative stress and prevent subsequent cell death in models of adult, neonatal and pediatric brain injury. ALCAR can provide an acetyl moiety that can be oxidized for energy, used as a precursor for acetylcholine, or incorporated into glutamate, glutamine and GABA, or into lipids for myelination and cell growth. Administration of ALCAR after brain injury in rat pups improved long-term functional outcomes, including memory. Additional studies are needed to better explore the potential of L-carnitine and ALCAR for protection of developing brain as there is an urgent need for therapies that can improve outcome after neonatal and pediatric brain injury.

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Section: Neuroprotection Afforded By L-carnitine Supplementation In Pmentioning

confidence: 99%

l-Carnitine and Acetyl-l-carnitine Roles and Neuroprotection in Developing Brain

2017

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“…Table 4 shows that medium-chain fatty acids accumulating in MCAD deficiency deregulate various crucial mitochondrial functions in brain, liver and skeletal muscle. It can be observed in the table that the medium-chain fatty acids inhibit energy production, utilization and transfer [ 102 – 106 ], uncouple OXPHOS [ 107 – 109 ] and induce oxidative stress [ 106 , 110 , 111 ], which may result at least partly from the blockage of the respiratory chain stimulating superoxide and other ROS production. The deleterious effects were more pronounced with decanoic acid and cis -4-decenoic acid, that also induced mPT, a condition that compromise all mitochondrial functions, including energy production, maintenance of cellular redox status and Ca 2+ retention capacity, culminating in cell death [ 112 ].…”

Section: Toxicity Of the Major Metabolites Accumulating In Faodmentioning

confidence: 99%

Mitochondrial dysfunction in fatty acid oxidation disorders: insights from human and animal studies

2016

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“…It is presumed that this pathomechanism possibly contribute to the chronic and neurologic symptoms seen in these defects. Moreover, although it is difficult to evaluate the relative contribution of the toxic fatty acids in the neuropathology of these diseases, it is conceivable that there may be a synergistic action between the toxicity of these Metabolic inhibition 54,55 Decrease of NAD(P)H content 54,55 Respiratory chain and creatine kinase activities inhibition 54,[56][57][58] Induction of oxidative stress 52,53 Decrease of Ca 2þ retention capacity 56 Induction of permeability transition 56 metabolites, hyperammonemia, and hypoketotic hypoglycemia (energy deficit) leading to brain damage. It is expected that the development of new drugs targeting the mitochondrion, initially in animal models and thereafter as adjuvant therapeutic approaches for the patients, may become an important focus in the future.…”

Section: Discussionmentioning

confidence: 99%

“…It has been demonstrated that MCFA, particularly decanoic and cis-4-decenoic acids, behave as uncouplers of OXPHOS and metabolic inhibitors, as well as inductors of mitochondrial permeability transition and oxidative stress. [51][52][53][54][55][56] These effects may be associated at least partly with the blockage of the respiratory chain provoked by MCFA that may stimulate superoxide and other ROS production 54,[56][57][58] and with the protonophoric action of these fatty acids due to the transbilayer movement of undissociated (linked to protons) fatty acids through the mitochondrial inner membrane toward the mitochondrial matrix. 59,60 Mitochondrial dysfunction has also been suggested as an important pathomechanism involved in the neurological symptoms that affect individuals with LCHAD deficiency since there are clear human evidences of mitochondrial damage in these patients.…”

Section: Evidence That Mitochondrial Dysfunction Is Caused By the Majmentioning

confidence: 99%

Mechanistic Bases of Neurotoxicity Provoked by Fatty Acids Accumulating in MCAD and LCHAD Deficiencies

Amaral

Cecatto

Silva

et al. 2017

Journal of Inborn Errors of Metabolism and Screening

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Fatty acid oxidation defects (FAODs) are inherited metabolic disorders caused by deficiency of specific enzyme activities or transport proteins involved in the mitochondrial catabolism of fatty acids. Medium-chain fatty acyl-CoA dehydrogenase (MCAD) and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiencies are relatively common FAOD biochemically characterized by tissue accumulation of medium-chain fatty acids and long-chain 3-hydroxy fatty acids and their carnitine derivatives, respectively. Patients with MCAD deficiency usually have episodic encephalopathic crises and liver biochemical alterations especially during crises of metabolic decompensation, whereas patients with LCHAD deficiency present severe hepatopathy, cardiomyopathy, and acute and/or progressive encephalopathy. Although neurological symptoms are common features, the underlying mechanisms responsible for the brain damage in these disorders are still under debate. In this context, energy deficiency due to defective fatty acid catabolism and hypoglycemia/hypoketonemia has been postulated to contribute to the pathophysiology of MCAD and LCHAD deficiencies. However, since energetic substrate supplementation is not able to reverse or prevent symptomatology in some patients, it is presumed that other pathogenetic mechanisms are implicated. Since worsening of clinical symptoms during crises is accompanied by significant increases in the concentrations of the accumulating fatty acids, it is conceivable that these compounds may be potentially neurotoxic. We will briefly summarize the current knowledge obtained from patients with these disorders, as well as from animal studies demonstrating deleterious effects of the major fatty acids accumulating in MCAD and LCHAD deficiencies, indicating that disruption of mitochondrial energy, redox, and calcium homeostasis is involved in the pathophysiology of the cerebral damage in these diseases. It is presumed that these findings based on the mechanistic toxic effects of fatty acids may offer new therapeutic perspectives for patients affected by these disorders.

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cis-4-decenoic acid provokes mitochondrial bioenergetic dysfunction in rat brain

Abstract: It is therefore presumed that impairment of mitochondrial homeostasis provoked by cis-4-decenoic acid may be involved in the brain dysfunction observed in medium-chain acyl-CoA dehydrogenase deficient patients.

Cited by 11 publications

References 48 publications

l-Carnitine and Acetyl-l-carnitine Roles and Neuroprotection in Developing Brain

l-Carnitine and Acetyl-l-carnitine Roles and Neuroprotection in Developing Brain

Mitochondrial dysfunction in fatty acid oxidation disorders: insights from human and animal studies

Mechanistic Bases of Neurotoxicity Provoked by Fatty Acids Accumulating in MCAD and LCHAD Deficiencies

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