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Article ; Online: Pathophysiology of maple syrup urine disease: Focus on the neurotoxic role of the accumulated branched-chain amino acids and branched-chain α-keto acids.

Amaral, Alexandre Umpierrez / Wajner, Moacir

2022 Volume 157, Page(s) 105360

Abstract: Maple syrup urine disease (MSUD) is an autosomal recessive neurometabolic disorder caused by severe deficiency of branched-chain α-keto acid dehydrogenase complex activity, which catalyzes the oxidative decarboxylation of the branched-chain α-keto acids ( ...

Abstract	Maple syrup urine disease (MSUD) is an autosomal recessive neurometabolic disorder caused by severe deficiency of branched-chain α-keto acid dehydrogenase complex activity, which catalyzes the oxidative decarboxylation of the branched-chain α-keto acids (BCKA). The metabolic blockage results in tissue accumulation and high urinary excretion of the branched-chain amino acids (BCAA) leucine, isoleucine and valine, as well as alloisoleucine, and their respective BCKA α-ketoisocaproic (α-KIC), α-ketoisovaleric and α-keto-β-methylvaleric acids. Affected patients usually manifest acute episodes of encephalopathy associated with seizures, coma and life-threatening cerebral edema in the first weeks of life, which is followed by progressive neurological deterioration with motor delay, ataxia, intellectual disability and psychiatric symptoms. The pathophysiology of the brain damage in MSUD has been mainly focused on brain amino acid imbalance leading to deficient cerebral protein and neurotransmitter synthesis. However, the acute episodes of severe neurological symptoms accompanied by large increases of BCKA/BCAA levels suggest neurotoxic actions of these compounds. In this particular, mounting evidence from humans and animal models support an important role of particularly leucine and α-KIC on the pathogenesis of the brain injury in MSUD. In this review we will present the current knowledge of the major mechanisms presumably involved in MSUD neuropathology and highlight the neurotoxic properties of the BCAA and BCKA, disturbing brain bioenergetics and redox homeostasis, besides inducing neuroinflammation. We suggest that these pathomechanisms may contribute to the neurological sequelae of MSUD patients and hopefully allow the design of novel therapeutic strategies, including antioxidant and bioenergetics stimulating drugs targeting the mitochondria.
MeSH term(s)	Amino Acids ; Amino Acids, Branched-Chain/metabolism ; Animals ; Humans ; Keto Acids/pharmacology ; Leucine/metabolism ; Maple Syrup Urine Disease/metabolism ; Neurotoxicity Syndromes
Chemical Substances	Amino Acids ; Amino Acids, Branched-Chain ; Keto Acids ; Leucine (GMW67QNF9C)
Language	English
Publishing date	2022-05-13
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	283190-9
ISSN	1872-9754 ; 0197-0186
ISSN (online)	1872-9754
ISSN	0197-0186
DOI	10.1016/j.neuint.2022.105360
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Article: Recent Advances in the Pathophysiology of Fatty Acid Oxidation Defects: Secondary Alterations of Bioenergetics and Mitochondrial Calcium Homeostasis Caused by the Accumulating Fatty Acids.

Amaral, Alexandre Umpierrez / Wajner, Moacir

Frontiers in genetics

2020 Volume 11, Page(s) 598976

Abstract: Deficiencies of medium-chain acyl-CoA dehydrogenase, mitochondrial trifunctional protein, isolated long-chain 3-hydroxyacyl-CoA dehydrogenase, and very long-chain acyl-CoA dehydrogenase activities are considered the most frequent fatty acid oxidation ... ...

Abstract	Deficiencies of medium-chain acyl-CoA dehydrogenase, mitochondrial trifunctional protein, isolated long-chain 3-hydroxyacyl-CoA dehydrogenase, and very long-chain acyl-CoA dehydrogenase activities are considered the most frequent fatty acid oxidation defects (FAOD). They are biochemically characterized by the accumulation of medium-chain, long-chain hydroxyl, and long-chain fatty acids and derivatives, respectively, in tissues and biological fluids of the affected patients. Clinical manifestations commonly include hypoglycemia, cardiomyopathy, and recurrent rhabdomyolysis. Although the pathogenesis of these diseases is still poorly understood, energy deprivation secondary to blockage of fatty acid degradation seems to play an important role. However, recent evidence indicates that the predominant fatty acids accumulating in these disorders disrupt mitochondrial functions and are involved in their pathophysiology, possibly explaining the lactic acidosis, mitochondrial morphological alterations, and altered mitochondrial biochemical parameters found in tissues and cultured fibroblasts from some affected patients and also in animal models of these diseases. In this review, we will update the present knowledge on disturbances of mitochondrial bioenergetics, calcium homeostasis, uncoupling of oxidative phosphorylation, and mitochondrial permeability transition induction provoked by the major fatty acids accumulating in prevalent FAOD. It is emphasized that further
Language	English
Publishing date	2020-11-27
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2606823-0
ISSN	1664-8021
ISSN	1664-8021
DOI	10.3389/fgene.2020.598976
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Article: Disruption of mitochondrial functions and oxidative stress contribute to neurologic dysfunction in organic acidurias

Wajner, Moacir / Vargas, Carmen Regla / Amaral, Alexandre Umpierrez

Archives of biochemistry and biophysics. 2020 Dec. 15, v. 696

2020

Abstract: Organic acidurias (OADs) are inherited disorders of amino acid metabolism biochemically characterized by accumulation of short-chain carboxylic acids in tissues and biological fluids of the affected patients and clinically by predominant neurological ... ...

Abstract	Organic acidurias (OADs) are inherited disorders of amino acid metabolism biochemically characterized by accumulation of short-chain carboxylic acids in tissues and biological fluids of the affected patients and clinically by predominant neurological manifestations. Some of these disorders are amenable to treatment, which significantly decreases mortality and morbidity, but it is still ineffective to prevent long-term neurologic and systemic complications. Although pathogenesis of OADs is still poorly established, recent human and animal data, such as lactic acidosis, mitochondrial morphological alterations, decreased activities of respiratory chain complexes and altered parameters of oxidative stress, found in tissues from patients and from genetic mice models with these diseases indicate that disruption of critical mitochondrial functions and oxidative stress play an important role in their pathophysiology. Furthermore, organic acids that accumulate in the most prevalent OADs were shown to compromise bioenergetics, by decreasing ATP synthesis, mitochondrial membrane potential, reducing equivalent content and calcium retention capacity, besides inducing mitochondrial swelling, reactive oxygen and nitrogen species generation and apoptosis. It is therefore presumed that secondary mitochondrial dysfunction and oxidative stress caused by major metabolites accumulating in OADs contribute to tissue damage in these pathologies.
Keywords	acidosis ; amino acid metabolism ; apoptosis ; biophysics ; calcium ; electron transport chain ; humans ; membrane potential ; metabolites ; mitochondria ; mitochondrial membrane ; morbidity ; mortality ; nitrogen ; oxidative stress ; oxygen ; pathogenesis ; pathophysiology
Language	English
Dates of publication	2020-1215
Publishing place	Elsevier Inc.
Document type	Article
Note	NAL-AP-2-clean
ZDB-ID	523-x
ISSN	1096-0384 ; 0003-9861
ISSN (online)	1096-0384
ISSN	0003-9861
DOI	10.1016/j.abb.2020.108646
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Article ; Online: Disruption of mitochondrial functions and oxidative stress contribute to neurologic dysfunction in organic acidurias.

Wajner, Moacir / Vargas, Carmen Regla / Amaral, Alexandre Umpierrez

Archives of biochemistry and biophysics

2020 Volume 696, Page(s) 108646

Abstract	Organic acidurias (OADs) are inherited disorders of amino acid metabolism biochemically characterized by accumulation of short-chain carboxylic acids in tissues and biological fluids of the affected patients and clinically by predominant neurological manifestations. Some of these disorders are amenable to treatment, which significantly decreases mortality and morbidity, but it is still ineffective to prevent long-term neurologic and systemic complications. Although pathogenesis of OADs is still poorly established, recent human and animal data, such as lactic acidosis, mitochondrial morphological alterations, decreased activities of respiratory chain complexes and altered parameters of oxidative stress, found in tissues from patients and from genetic mice models with these diseases indicate that disruption of critical mitochondrial functions and oxidative stress play an important role in their pathophysiology. Furthermore, organic acids that accumulate in the most prevalent OADs were shown to compromise bioenergetics, by decreasing ATP synthesis, mitochondrial membrane potential, reducing equivalent content and calcium retention capacity, besides inducing mitochondrial swelling, reactive oxygen and nitrogen species generation and apoptosis. It is therefore presumed that secondary mitochondrial dysfunction and oxidative stress caused by major metabolites accumulating in OADs contribute to tissue damage in these pathologies.
MeSH term(s)	Amino Acid Metabolism, Inborn Errors/complications ; Amino Acid Metabolism, Inborn Errors/physiopathology ; Animals ; Brain/metabolism ; Carboxylic Acids/metabolism ; Humans ; Mitochondria/metabolism ; Nervous System Diseases/etiology ; Nervous System Diseases/physiopathology ; Oxidative Stress/physiology
Chemical Substances	Carboxylic Acids
Language	English
Publishing date	2020-10-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	523-x
ISSN	1096-0384 ; 0003-9861
ISSN (online)	1096-0384
ISSN	0003-9861
DOI	10.1016/j.abb.2020.108646
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Article ; Online: Disturbance of mitochondrial functions caused by N-acetylglutamate and N-acetylmethionine in brain of adolescent rats: Potential relevance in aminoacylase 1 deficiency.

Bortoluzzi, Vanessa Trindade / Ribeiro, Rafael Teixeira / Zemniaçak, Ângela Beatris / Cunha, Sâmela de Azevedo / Sass, Jörn Oliver / Castilho, Roger Frigério / Amaral, Alexandre Umpierrez / Wajner, Moacir

Neurochemistry international

2023 Volume 171, Page(s) 105631

Abstract: Aminoacylase 1 (ACY1) deficiency is a rare genetic disorder that affects the breakdown of short-chain aliphatic N-acetylated amino acids, leading to the accumulation of these amino acid derivatives in the urine of patients. Some of the affected ... ...

Abstract	Aminoacylase 1 (ACY1) deficiency is a rare genetic disorder that affects the breakdown of short-chain aliphatic N-acetylated amino acids, leading to the accumulation of these amino acid derivatives in the urine of patients. Some of the affected individuals have presented with heterogeneous neurological symptoms such as psychomotor delay, seizures, and intellectual disability. Considering that the pathological mechanisms of brain damage in this disorder remain mostly unknown, here we investigated whether major metabolites accumulating in ACY1 deficiency, namely N-acetylglutamate (NAG) and N-acetylmethionine (NAM), could be toxic to the brain by examining their in vitro effects on important mitochondrial properties. We assessed the effects of NAG and NAM on membrane potential, swelling, reducing equivalents, and Ca
MeSH term(s)	Animals ; Rats ; Brain/metabolism ; Calcium/metabolism ; Energy Metabolism ; Fatty Acids/metabolism ; Glutamates/pharmacology ; Mitochondria/metabolism ; Mitochondrial Permeability Transition Pore/metabolism ; Mitochondrial Permeability Transition Pore/pharmacology ; Aging
Chemical Substances	Calcium (SY7Q814VUP) ; Fatty Acids ; Glutamates ; Mitochondrial Permeability Transition Pore ; N-acetylglutamic acid (MA61H539YZ) ; N-acetylmethionine (9J12WX5B6A)
Language	English
Publishing date	2023-10-16
Publishing country	England
Document type	Journal Article
ZDB-ID	283190-9
ISSN	1872-9754 ; 0197-0186
ISSN (online)	1872-9754
ISSN	0197-0186
DOI	10.1016/j.neuint.2023.105631
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Article ; Online: Disruption of mitochondrial bioenergetics and calcium homeostasis by phytanic acid in the heart: Potential relevance for the cardiomyopathy in Refsum disease.

Zemniaçak, Ângela Beatriz / Roginski, Ana Cristina / Ribeiro, Rafael Teixeira / Bender, Julia Gabrieli / Marschner, Rafael Aguiar / Wajner, Simone Magagnin / Wajner, Moacir / Amaral, Alexandre Umpierrez

Biochimica et biophysica acta. Bioenergetics

2023 Volume 1864, Issue 2, Page(s) 148961

Abstract: Refsum disease is an inherited peroxisomal disorder caused by severe deficiency of phytanoyl-CoA hydroxylase activity. Affected patients develop severe cardiomyopathy of poorly known pathogenesis that may lead to a fatal outcome. Since phytanic acid ( ... ...

Abstract	Refsum disease is an inherited peroxisomal disorder caused by severe deficiency of phytanoyl-CoA hydroxylase activity. Affected patients develop severe cardiomyopathy of poorly known pathogenesis that may lead to a fatal outcome. Since phytanic acid (Phyt) concentrations are highly increased in tissues of individuals with this disease, it is conceivable that this branched-chain fatty acid is cardiotoxic. The present study investigated whether Phyt (10-30 μM) could disturb important mitochondrial functions in rat heart mitochondria. We also determined the influence of Phyt (50-100 μM) on cell viability (MTT reduction) in cardiac cells (H9C2). Phyt markedly increased mitochondrial state 4 (resting) and decreased state 3 (ADP-stimulated) and uncoupled (CCCP-stimulated) respirations, besides reducing the respiratory control ratio, ATP synthesis and the activities of the respiratory chain complexes I-III, II, and II-III. This fatty acid also reduced mitochondrial membrane potential and induced swelling in mitochondria supplemented by exogenous Ca
MeSH term(s)	Rats ; Animals ; Refsum Disease/metabolism ; Phytanic Acid/pharmacology ; Phytanic Acid/metabolism ; Calcium/metabolism ; Rats, Wistar ; Cardiomyopathies/drug therapy ; Cardiomyopathies/metabolism ; Energy Metabolism ; Mitochondria, Heart/metabolism ; Fatty Acids/metabolism ; Mitochondrial Permeability Transition Pore/metabolism ; Homeostasis
Chemical Substances	Phytanic Acid (14721-66-5) ; Calcium (SY7Q814VUP) ; Fatty Acids ; Mitochondrial Permeability Transition Pore
Language	English
Publishing date	2023-02-20
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	60-7
ISSN	1879-2650 ; 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-2650 ; 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbabio.2023.148961
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Article ; Online: Disruption of mitochondrial bioenergetics and calcium homeostasis by phytanic acid in the heart: Potential relevance for the cardiomyopathy in Refsum disease

BBA - Bioenergetics. 2023 Apr., v. 1864, no. 2 p.148961-

2023

Abstract	Refsum disease is an inherited peroxisomal disorder caused by severe deficiency of phytanoyl-CoA hydroxylase activity. Affected patients develop severe cardiomyopathy of poorly known pathogenesis that may lead to a fatal outcome. Since phytanic acid (Phyt) concentrations are highly increased in tissues of individuals with this disease, it is conceivable that this branched-chain fatty acid is cardiotoxic. The present study investigated whether Phyt (10–30 μM) could disturb important mitochondrial functions in rat heart mitochondria. We also determined the influence of Phyt (50–100 μM) on cell viability (MTT reduction) in cardiac cells (H9C2). Phyt markedly increased mitochondrial state 4 (resting) and decreased state 3 (ADP-stimulated) and uncoupled (CCCP-stimulated) respirations, besides reducing the respiratory control ratio, ATP synthesis and the activities of the respiratory chain complexes I-III, II, and II-III. This fatty acid also reduced mitochondrial membrane potential and induced swelling in mitochondria supplemented by exogenous Ca²⁺, which were prevented by cyclosporin A alone or combined with ADP, suggesting the involvement of the mitochondrial permeability transition (MPT) pore opening. Mitochondrial NAD(P)H content and Ca²⁺ retention capacity were also decreased by Phyt in the presence of Ca²⁺. Finally, Phyt significantly reduced cellular viability (MTT reduction) in cultured cardiomyocytes. The present data indicate that Phyt, at concentrations found in the plasma of patients with Refsum disease, disrupts by multiple mechanisms mitochondrial bioenergetics and Ca²⁺ homeostasis, which could presumably be involved in the cardiomyopathy of this disease.
Keywords	branched chain fatty acids ; calcium ; cardiomyocytes ; cardiomyopathy ; cell viability ; cyclosporine ; electron transport chain ; homeostasis ; membrane potential ; mitochondria ; mitochondrial membrane ; pathogenesis ; permeability ; rats ; AU ; ANOVA ; ANT ; ATC ; BSA ; CCCP ; CsA ; DCIP ; DMSO ; EGTA ; FAU ; HEPES ; H2O2 ; ΔΨm ; MOPS ; MPT ; MTT ; Phyt ; RCR ; SDH ; Refsum disease ; Phytanic acid ; Mitochondrial bioenergetics ; Ca2+ homeostasis ; Mitochondrial permeability transition
Language	English
Dates of publication	2023-04
Publishing place	Elsevier B.V.
Document type	Article ; Online
ZDB-ID	282711-6
ISSN	0005-2728 ; 0304-4173
ISSN	0005-2728 ; 0304-4173
DOI	10.1016/j.bbabio.2023.148961
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Article ; Online: Disruption of mitochondrial bioenergetics, calcium retention capacity and cell viability caused by D-2-hydroxyglutaric acid in the heart

Ribeiro, Rafael Teixeira / Roginski, Ana Cristina / Marschner, Rafael Aguiar / Wajner, Simone Magagnin / Castilho, Roger Frigério / Amaral, Alexandre Umpierrez / Wajner, Moacir

Biochimie. 2023 Apr., v. 207 p.153-164

2023

Abstract: Accumulation of D-2-hydroxyglutaric acid (D-2-HG) is the biochemical hallmark of D-2-hydroxyglutaric aciduria type I and, particularly, of D-2-hydroxyglutaric aciduria type II (D2HGA2). D2HGA2 is a metabolic inherited disease caused by gain-of-function ... ...

Abstract	Accumulation of D-2-hydroxyglutaric acid (D-2-HG) is the biochemical hallmark of D-2-hydroxyglutaric aciduria type I and, particularly, of D-2-hydroxyglutaric aciduria type II (D2HGA2). D2HGA2 is a metabolic inherited disease caused by gain-of-function mutations in the gene isocitrate dehydrogenase 2. It is clinically characterized by neurological abnormalities and a severe cardiomyopathy whose pathogenesis is still poorly established. The present work investigated the potential cardiotoxicity D-2-HG, by studying its in vitro effects on a large spectrum of bioenergetics parameters in heart of young rats and in cultivated H9c2 cardiac myoblasts. D-2-HG impaired cellular respiration in purified mitochondrial preparations and crude homogenates from heart of young rats, as well as in digitonin-permeabilized H9c2 cells. ATP production and the activities of cytochrome c oxidase (complex IV), alpha-ketoglutarate dehydrogenase, citrate synthase and creatine kinase were also inhibited by D-2-HG, whereas the activities of complexes I, II and II-III of the respiratory chain, glutamate, succinate and malate dehydrogenases were not altered. We also found that this organic acid compromised mitochondrial Ca²⁺ retention capacity in heart mitochondrial preparations and H9c2 myoblasts. Finally, D-2-HG reduced the viability of H9c2 cardiac myoblasts, as determined by the MTT test and by propidium iodide incorporation. Noteworthy, L-2-hydroxyglutaric acid did not change some of these measurements (complex IV and creatine kinase activities) in heart preparations, indicating a selective inhibitory effect of the enantiomer D. In conclusion, it is presumed that D-2-HG-disrupts mitochondrial bioenergetics and Ca²⁺ retention capacity, which may be involved in the cardiomyopathy commonly observed in D2HGA2.
Keywords	calcium ; cardiomyopathy ; cardiotoxicity ; cell respiration ; cell viability ; citrate (si)-synthase ; creatine kinase ; electron transport chain ; enantiomers ; gain-of-function mutation ; genes ; genetic disorders ; glutamic acid ; heart ; isocitrate dehydrogenase ; malates ; mitochondria ; myoblasts ; oxoglutarate dehydrogenase (succinyl-transferring) ; pathogenesis ; propidium ; succinic acid ; D-2-Hydroxyglutaric aciduria ; D-2-Hydroxyglutaric acid ; Bioenergetics dysfunction
Language	English
Dates of publication	2023-04
Size	p. 153-164.
Publishing place	Elsevier B.V.
Document type	Article ; Online
ZDB-ID	120345-9
ISSN	0300-9084
ISSN	0300-9084
DOI	10.1016/j.biochi.2022.11.004
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Article ; Online: Disturbances in mitochondrial bioenergetics and control quality and unbalanced redox homeostasis in the liver of a mouse model of mucopolysaccharidosis type II.

Pinheiro, Camila Vieira / Ribeiro, Rafael Teixeira / Roginski, Ana Cristina / Brondani, Morgana / Zemniaçak, Ângela Beatris / Hoffmann, Chrístofer Ian Hernandez / Amaral, Alexandre Umpierrez / Wajner, Moacir / Baldo, Guilherme / Leipnitz, Guilhian

Molecular and cellular biochemistry

2024

Abstract: Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is a lysosomal storage disease caused by mutations in the gene encoding the enzyme iduronate 2-sulfatase (IDS) and biochemically characterized by the accumulation of glycosaminoglycans (GAGs) in ... ...

Abstract	Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is a lysosomal storage disease caused by mutations in the gene encoding the enzyme iduronate 2-sulfatase (IDS) and biochemically characterized by the accumulation of glycosaminoglycans (GAGs) in different tissues. It is a multisystemic disorder that presents liver abnormalities, the pathophysiology of which is not yet established. In the present study, we evaluated bioenergetics, redox homeostasis, and mitochondrial dynamics in the liver of 6-month-old MPS II mice (IDS
Language	English
Publishing date	2024-03-18
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	184833-1
ISSN	1573-4919 ; 0300-8177
ISSN (online)	1573-4919
ISSN	0300-8177
DOI	10.1007/s11010-024-04952-y
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Article ; Online: Mitochondrial dysfunction in fatty acid oxidation disorders: insights from human and animal studies.

Wajner, Moacir / Amaral, Alexandre Umpierrez

Bioscience reports

2015 Volume 36, Issue 1, Page(s) e00281

Abstract: Mitochondrial fatty acid oxidation (FAO) plays a pivotal role in maintaining body energy homoeostasis mainly during catabolic states. Oxidation of fatty acids requires approximately 25 proteins. Inherited defects of FAO have been identified in the ... ...

Abstract	Mitochondrial fatty acid oxidation (FAO) plays a pivotal role in maintaining body energy homoeostasis mainly during catabolic states. Oxidation of fatty acids requires approximately 25 proteins. Inherited defects of FAO have been identified in the majority of these proteins and constitute an important group of inborn errors of metabolism. Affected patients usually present with severe hepatopathy, cardiomyopathy and skeletal myopathy, whereas some patients may suffer acute and/or progressive encephalopathy whose pathogenesis is poorly known. In recent years growing evidence has emerged indicating that energy deficiency/disruption of mitochondrial homoeostasis is involved in the pathophysiology of some fatty acid oxidation defects (FAOD), although the exact underlying mechanisms are not yet established. Characteristic fatty acids and carnitine derivatives are found at high concentrations in these patients and more markedly during episodes of metabolic decompensation that are associated with worsening of clinical symptoms. Therefore, it is conceivable that these compounds may be toxic. We will briefly summarize the current knowledge obtained from patients and genetic mouse models with these disorders indicating that disruption of mitochondrial energy, redox and calcium homoeostasis is involved in the pathophysiology of the tissue damage in the more common FAOD, including medium-chain acyl-CoA dehydrogenase (MCAD), long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) and very long-chain acyl-CoA dehydrogenase (VLCAD) deficiencies. We will also provide evidence that the fatty acids and derivatives that accumulate in these diseases disrupt mitochondrial homoeostasis. The elucidation of the toxic mechanisms of these compounds may offer new perspectives for potential novel adjuvant therapeutic strategies in selected disorders of this group.
MeSH term(s)	Animals ; Cardiomyopathies/genetics ; Cardiomyopathies/metabolism ; Fatty Acids/genetics ; Fatty Acids/metabolism ; Humans ; Lipid Metabolism Disorders/genetics ; Lipid Metabolism Disorders/metabolism ; Liver Diseases/genetics ; Liver Diseases/metabolism ; Mice ; Mitochondria/genetics ; Mitochondria/metabolism ; Mitochondrial Diseases/genetics ; Mitochondrial Diseases/metabolism ; Oxidation-Reduction
Chemical Substances	Fatty Acids
Language	English
Publishing date	2015-11-20
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	764946-0
ISSN	1573-4935 ; 0144-8463
ISSN (online)	1573-4935
ISSN	0144-8463
DOI	10.1042/BSR20150240
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