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

Amaral, Alexandre Umpierrez; Cecatto, Cristiane; Silva, Janaína C. da; Wajner, Alessandro; Wajner, Moaçir

doi:10.1177/2326409817701472

Cited by 4 publications

(3 citation statements)

References 73 publications

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“…Oxidative stress It is induced by accumulation of LC hydroxylated acylcarnitines and results in mitochondrial damage. 40 Alteration of cardiolipin profile Mature cardiolipin (CL) is an essential constituent of mitochondrial membranes. It functions in organising the cristae and electron transport chain (ETC) higher order structure, important for ETC activity, and acts as a proton trap on the outer leaflet of the inner mitochondrial membrane.…”

Section: Pathophysiologymentioning

confidence: 99%

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Fifty years of research on mitochondrial fatty acid oxidation disorders: The remaining challenges

Vianey‐Saban,

Guffon,

Fouilhoux

et al. 2023

J of Inher Metab Disea

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Since the identification of the first disorder of mitochondrial fatty acid oxidation (FAOD) in 1973, more than twenty defects have been identified. Although there are some differences, most FAOD have similar clinical signs, which are mainly due to energy depletion and toxicity of accumulated metabolites. However, some of them have an unusual clinical phenotype or specific clinical signs. This manuscript focuses on what we have learnt so far on the pathophysiology of these disorders which present with clinical signs that are not typical of categorical FAOD. It also highlights that some disorders have not yet been identified and tries to make assumptions to explain why. It also deals with new treatments under consideration in FAOD, including triheptanoin and similar anaplerotic substrates, ketone body treatments, RNA and gene therapy approaches. Finally, it suggests challenges for the diagnosis of FAOD in the coming years, both for symptomatic patients and for those diagnosed through newborn screening. The ultimate goal would be to identify all the patients born with FAOD and ensure for them the best possible quality of life.Take home messageTentative hypotheses to improve the diagnosis and the treatment of fatty acid oxidation defects.This article is protected by copyright. All rights reserved.

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Section: Pathophysiologymentioning

confidence: 99%

“…It is induced by accumulation of LC hydroxylated acylcarnitines and results in mitochondrial damage 40 …”

Section: Understanding the Pathophysiology Of Unusual Clinical Signsmentioning

confidence: 99%

Fifty years of research on mitochondrial fatty acid oxidation disorders: The remaining challenges

Vianey‐Saban,

Guffon,

Fouilhoux

et al. 2023

J of Inher Metab Disea

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“…Based on these observations, here we propose a comprehensive pathomechanism for the progressive neurodegeneration in LCHADD/MTPD that includes the experimental evidence reported in the past years (Figure 1). First, oxidative stress induced by the accumulation of long-chain hydroxy acylcarnitines and hampered electron flow results in mitochondrial damage [68]. This is aggravated by the altered content and composition of mitochondrial cardiolipins as a consequence of the accumulation of long-chain fatty acids that cannot enter the β-oxidation cycle [7].…”

Section: Sphingomyelins and Ceramides: New Co-player For Neurodegener...mentioning

confidence: 99%

An Altered Sphingolipid Profile as a Risk Factor for Progressive Neurodegeneration in Long-Chain 3-Hydroxyacyl-CoA Deficiency (LCHADD)

Tucci

2022

IJMS

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Long-chain 3-hydroxyacyl-CoA deficiency (LCHADD) and mitochondrial trifunctional protein (MTPD) belong to a group of inherited metabolic diseases affecting the degradation of long-chain chain fatty acids. During metabolic decompensation the incomplete degradation of fatty acids results in life-threatening episodes, coma and death. Despite fast identification at neonatal screening, LCHADD/MTPD present with progressive neurodegenerative symptoms originally attributed to the accumulation of toxic hydroxyl acylcarnitines and energy deficiency. Recently, it has been shown that LCHADD human fibroblasts display a disease-specific alteration of complex lipids. Accumulating fatty acids, due to defective β-oxidation, contribute to a remodeling of several lipid classes including mitochondrial cardiolipins and sphingolipids. In the last years the face of LCHADD/MTPD has changed. The reported dysregulation of complex lipids other than the simple acylcarnitines represents a novel aspect of disease development. Indeed, aberrant lipid profiles have already been associated with other neurodegenerative diseases such as Parkinson’s Disease, Alzheimer’s Disease, amyotrophic lateral sclerosis and retinopathy. Today, the physiopathology that underlies the development of the progressive neuropathic symptoms in LCHADD/MTPD is not fully understood. Here, we hypothesize an alternative disease-causing mechanism that contemplates the interaction of several factors that acting in concert contribute to the heterogeneous clinical phenotype.

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Transcriptome analysis suggests a compensatory role of the cofactors coenzyme A and NAD+ in medium-chain acyl-CoA dehydrogenase knockout mice

Martines

Gerding

Stolle

et al. 2019

Sci Rep

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During fasting, mitochondrial fatty-acid β-oxidation (mFAO) is essential for the generation of glucose by the liver. Children with a loss-of-function deficiency in the mFAO enzyme medium-chain acyl-Coenzyme A dehydrogenase (MCAD) are at serious risk of life-threatening low blood glucose levels during fasting in combination with intercurrent disease. However, a subset of these children remains asymptomatic throughout life. In MCAD-deficient (MCAD-KO) mice, glucose levels are similar to those of wild-type (WT) mice, even during fasting. We investigated if metabolic adaptations in the liver may underlie the robustness of this KO mouse. WT and KO mice were given a high- or low-fat diet and subsequently fasted. We analyzed histology, mitochondrial function, targeted mitochondrial proteomics, and transcriptome in liver tissue. Loss of MCAD led to a decreased capacity to oxidize octanoyl-CoA. This was not compensated for by altered protein levels of the short- and long-chain isoenzymes SCAD and LCAD. In the transcriptome, we identified subtle adaptations in the expression of genes encoding enzymes catalyzing CoA- and NAD(P)(H)-involving reactions and of genes involved in detoxification mechanisms. We discuss how these processes may contribute to robustness in MCAD-KO mice and potentially also in asymptomatic human subjects with a complete loss of MCAD activity.

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

Cited by 4 publications

References 73 publications

Fifty years of research on mitochondrial fatty acid oxidation disorders: The remaining challenges

Fifty years of research on mitochondrial fatty acid oxidation disorders: The remaining challenges

An Altered Sphingolipid Profile as a Risk Factor for Progressive Neurodegeneration in Long-Chain 3-Hydroxyacyl-CoA Deficiency (LCHADD)

Transcriptome analysis suggests a compensatory role of the cofactors coenzyme A and NAD+ in medium-chain acyl-CoA dehydrogenase knockout mice

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