Evidence for the physical association of mitochondrial fatty acid oxidation and oxidative phosphorylation complexes

Wang, Yudong; Mohsen, Al-Walid; Mihalik, Stephanie J.; Goetzman, Eric S.; Vockley, Jerry

doi:10.1016/j.mito.2011.03.031

Cited by 28 publications

(38 citation statements)

References 20 publications

(23 reference statements)

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“…For example, Enns et al [] mentioned the possibility of the physical association between these two energy‐generating pathways from overlapping clinical phenotypes in genetic deficiency states. More recently, Wang and his colleagues actually showed physical association between mitochondrial fatty acid β‐oxidation enzymes and respiratory chain complexes (Wang et al., ). Similarly, Narayan et al demonstrated interactions between short‐chain 3‐hydroxyacyl‐CoA dehydrogenase (SCHAD) and several components of the respiratory chain complexes including the catalytic subunits of complexes I, II, III, and IV via pull‐down assays involving several mouse tissues.…”

Section: Discussionmentioning

confidence: 99%

ECHS1 Mutations Cause Combined Respiratory Chain Deficiency Resulting in Leigh Syndrome

et al. 2015

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The human ECHS1 gene encodes the short-chain enoyl coenzyme A hydratase, the enzyme that catalyzes the second step of β-oxidation of fatty acids in the mitochondrial matrix. We report on a boy with ECHS1 deficiency who was diagnosed with Leigh syndrome at 21 months of age. The patient presented with hypotonia, metabolic acidosis, and developmental delay. A combined respiratory chain deficiency was also observed. Targeted exome sequencing of 776 mitochondria-associated genes encoded by nuclear DNA identified compound heterozygous mutations in ECHS1. ECHS1 protein expression was severely depleted in the patient's skeletal muscle and patient-derived myoblasts; a marked decrease in enzyme activity was also evident in patient-derived myoblasts. Immortalized patient-derived myoblasts that expressed exogenous wild-type ECHS1 exhibited the recovery of the ECHS1 activity, indicating that the gene defect was pathogenic. Mitochondrial respiratory complex activity was also mostly restored in these cells, suggesting that there was an unidentified link between deficiency of ECHS1 and respiratory chain. Here, we describe the patient with ECHS1 deficiency; these findings will advance our understanding not only the pathology of mitochondrial fatty acid β-oxidation disorders, but also the regulation of mitochondrial metabolism.

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Section: Discussionmentioning

confidence: 99%

ECHS1 Mutations Cause Combined Respiratory Chain Deficiency Resulting in Leigh Syndrome

et al. 2015

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“…We have also demonstrated the direct, physical interaction of multifunctional fatty acid oxidation complex and the respiratory chain supercomplexes [31]. Thus the possible existence of non-enzymatic functions for both the mitochondrial and non-mitochondrial forms of ACAD10 and 11 must be considered in future studies.…”

Section: 0 Discussionmentioning

confidence: 99%

Identification and characterization of new long chain Acyl-CoA dehydrogenases

Pei²,

Mohsen

et al. 2011

Molecular Genetics and Metabolism

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Long-chain fatty acids are an important source of energy in muscle and heart where the acyl-CoA dehydrogenases (ACADs) participate in consecutive cycles of β-oxidation to generate acetyl-CoA and reducing equivalents for generating energy. However, the role of long-chain fatty acid oxidation in the brain and other tissues that do not rely on fat for energy is poorly understood. Here we characterize two new ACADs, ACAD10 and ACAD11, both with significant expression in human brain. ACAD11 utilizes substrates with primary carbon chain lengths between 20 and 26, with optimal activity towards C22CoA. The combination of ACAD11 with the newly characterized ACAD9 accommodates the full spectrum of long chain fatty acid substrates presented to mitochondrial β-oxidation in human cerebellum. ACAD10 has significant activity towards the branched-chain substrates R and S, 2 methyl-C15-CoA and is highly expressed in fetal but not adult brain. This pattern of expression is similar to that of LCAD, another ACAD previously shown to be involved in long branched chain fatty acid metabolism. Interestingly, the ACADs in human cerebellum were found to have restricted cellular distribution. ACAD9 was most highly expressed in the granular layer, ACAD11 in the white matter, and MCAD in the molecular layer and axons of specific neurons. This compartmentalization of ACADs in the human central nerve system, suggests that β-oxidation in cerebellum participates in different functions other than generating energy, for example, the synthesis and/or degradation of unique cellular lipids and catabolism of aromatic amino acids, compounds that are vital to neuronal function.

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“…An example in the context of mitochondria is the complexes and super-complexes of the respiratory chain (Reifschneider et al 2006) and the ongoing discussion about a complex comprising interacting enzymes of the mitochondrial fatty acid oxidation (Eaton 2002;Gregersen and Olsen 2010;Wang et al 2010). Several methods to isolate and analyze such complexes of interacting proteins using mass spectrometry have been developed (Kocher and Superti-Furga 2007).…”

Section: Current Development Of Mitochondrial Functional Proteomics-pmentioning

confidence: 99%

“…Several methods to isolate and analyze such complexes of interacting proteins using mass spectrometry have been developed (Kocher and Superti-Furga 2007). One approach is to use gradient centrifugation and/or blue native PAGE followed by either MS or antibody detection (Wang et al 2010). A second method is the classical affinity purification protocol either using chemical affinity or antibodies against a tag in one component to precipitate the whole complex and analyze it by mass spectrometry (Selbach and Mann 2006;Ewing et al 2007;Collins and Choudhary 2008;Suter et al 2008).…”

Section: Current Development Of Mitochondrial Functional Proteomics-pmentioning

confidence: 99%

Mitochondrial proteomics—a tool for the study of metabolic disorders

Gregersen

Hansen

Palmfeldt

2012

J of Inher Metab Disea

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Mitochondria are important for a number of life and death processes, such as energy production, creation of reactive oxygen species, and elicitation of stress responses. These responses range from induction of protein quality control and antioxidant systems to mitochondria elimination and cell death. Mitochondrial dysfunctions are involved in pathologies associated with many diseases, for example metabolic disorders, diabetes, cancers, cardiovascular and neurodegenerative diseases as well as obesity and aging. Mitochondrial proteomics can be a powerful tool in the study of these diseases, especially since it can cover mitochondrial proteins from several metabolic pathways, such as the citric acid cycle, fatty acid oxidation, and respiratory chain, as well as protein networks involved in stress responses. The mitochondrial proteome can consist of more than 1,000 different proteins. However, it is difficult to define the precise number, since mitochondria are dynamic and difficult to purify, and because an unknown number of proteins possess dual or multiple localization, depending on cell type and physiological conditions. This review describes several quantitative studies of proteins from mitochondria isolated by centrifugation, separated by various methods (e.g., electrophoresis and nanoLC), and analyzed by advanced mass spectrometry. We illustrate the methods by showing that multiple pathways and networks are affected in cells from patients carrying gene variations affecting a mitochondrial protein. The study of cultured skin fibroblasts from patients with ethylmalonic aciduria associated with variations in the genes coding for short-chain acyl-CoA dehydrogenase (SCAD) or ETHE1 are two of the examples. The possibility of obtaining mitochondrial proteomics data from whole cell proteomics studies is also exemplified by the involvement of liver mitochondria in metabolic syndrome.

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Evidence for the physical association of mitochondrial fatty acid oxidation and oxidative phosphorylation complexes

Cited by 28 publications

References 20 publications

ECHS1 Mutations Cause Combined Respiratory Chain Deficiency Resulting in Leigh Syndrome

ECHS1 Mutations Cause Combined Respiratory Chain Deficiency Resulting in Leigh Syndrome

Identification and characterization of new long chain Acyl-CoA dehydrogenases

Mitochondrial proteomics—a tool for the study of metabolic disorders

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