Loss of the Mitochondrial Fatty Acid β-Oxidation Protein Medium-Chain Acyl-Coenzyme A Dehydrogenase Disrupts Oxidative Phosphorylation Protein Complex Stability and Function

Lim, Sze Chern; Tajika, Makiko; Shimura, Masaru; Carey, Kirstyn T.; Stroud, David A.; Murayama, Kei; Ohtake, Akira; McKenzie, Matthew

doi:10.1038/s41598-017-18530-4

Cited by 49 publications

(43 citation statements)

References 43 publications

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“…Fibroblasts from MCAD‐deficient patients exhibit reduced carbohydrate oxidation, as well as decreased steady‐state levels of OXPHOS complexes I, III, IV and the OXPHOS supercomplex . In addition, assembly of OXPHOS subunits into de novo OXPHOS complexes was also disrupted in cells lacking MCAD expression . These findings highlight that the loss of MCAD is associated with a disruption of both OXPHOS complex assembly and stability, which subsequently contributes to defects in OXPHOS function.…”

Section: Emerging Links Between β‐Fao and Oxphos In Pathophysiologymentioning

confidence: 82%

“…Only one other study to date has investigated OXPHOS complex levels in ECHS1D, with no changes reported . It is currently unclear why the levels of complex IV were reduced in the patient reported by Tetreault et al ., but it can be hypothesized that ECHS1 may play some role in maintaining OXPHOS complex stability in a similar fashion to other FAO proteins such as MCAD and ACAD9 . As such, the loss of ECHS1 expression may result in the degradation of OXPHOS complex IV due to the loss of stabilizing physical interactions.…”

Section: Secondary Oxphos Defects In Echs1dmentioning

confidence: 99%

“…Furthermore, increased oxidative stress, due to the disruption of OXPHOS, may also be contributing to MCAD deficiency disease pathogenesis. Increased ROS production has been reported in patients with MCAD deficiency [86,87], while cells lacking MCAD expression exhibit elevated ROS generation associated with increased sensitivity to OXPHOS complex III inhibition [24].…”

Section: Emerging Links Between B-fao and Oxphos In Pathophysiologymentioning

confidence: 99%

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Understanding the role of OXPHOS dysfunction in the pathogenesis of ECHS1 deficiency

Burgin

McKenzie

2020

FEBS Letters

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Mitochondria provide the main source of energy for eukaryotic cells, oxidizing fatty acids and sugars to generate ATP. Mitochondrial fatty acid β‐oxidation (FAO) and oxidative phosphorylation (OXPHOS) are two key pathways involved in this process. Disruption of FAO can cause human disease, with patients commonly presenting with liver failure, hypoketotic glycaemia and rhabdomyolysis. However, patients with deficiencies in the FAO enzyme short‐chain enoyl‐CoA hydratase 1 (ECHS1) are typically diagnosed with Leigh syndrome, a lethal form of subacute necrotizing encephalomyelopathy that is normally associated with OXPHOS dysfunction. Furthermore, some ECHS1‐deficient patients also exhibit secondary OXPHOS defects. This sequela of FAO disorders has long been thought to be caused by the accumulation of inhibitory fatty acid intermediates. However, new evidence suggests that the mechanisms involved are more complex, and that disruption of OXPHOS protein complex biogenesis and/or stability is also involved. In this review, we examine the clinical, biochemical and genetic features of all ECHS1‐deficient patients described to date. In particular, we consider the secondary OXPHOS defects associated with ECHS1 deficiency and discuss their possible contribution to disease pathogenesis.

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Section: Emerging Links Between β‐Fao and Oxphos In Pathophysiologymentioning

confidence: 82%

Section: Secondary Oxphos Defects In Echs1dmentioning

confidence: 99%

Section: Emerging Links Between B-fao and Oxphos In Pathophysiologymentioning

confidence: 99%

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Understanding the role of OXPHOS dysfunction in the pathogenesis of ECHS1 deficiency

Burgin

McKenzie

2020

FEBS Letters

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“…B , Supporting Table 4). Furthermore, assessment of the acyl‐CoA dehydrogenase medium chain ( Acadm ) gene that catalyses the first step of the mitochondrial β‐oxidation pathway, impairments of which have been shown to activate oxidative stress, were not significantly different between the Polg2 +/+ and Polg2 +/Y265X mice (Fig. C , Supporting Table 4).…”

Section: Resultsmentioning

confidence: 99%

An N-Ethyl-N-Nitrosourea (ENU)-Induced Tyr265Stop Mutation of the DNA Polymerase Accessory Subunit Gamma 2 (Polg2) Is Associated With Renal Calcification in Mice

Gorvin

Ahmad

Stechman

et al. 2018

Journal of Bone and Mineral Research

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Renal calcification (RCALC) resulting in nephrolithiasis and nephrocalcinosis, which affects ∼10% of adults by 70 years of age, involves environmental and genetic etiologies. Thus, nephrolithiasis and nephrocalcinosis occurs as an inherited disorder in ∼65% of patients, and may be associated with endocrine and metabolic disorders including: primary hyperparathyroidism, hypercalciuria, renal tubular acidosis, cystinuria, and hyperoxaluria. Investigations of families with nephrolithiasis and nephrocalcinosis have identified some causative genes, but further progress is limited as large families are unavailable for genetic studies. We therefore embarked on establishing mouse models for hereditary nephrolithiasis and nephrocalcinosis by performing abdominal X‐rays to identify renal opacities in N‐ethyl‐N‐nitrosourea (ENU)‐mutagenized mice. This identified a mouse with RCALC inherited as an autosomal dominant trait, designated RCALC type 2 (RCALC2). Genomewide mapping located the Rcalc2 locus to a ∼16‐Mbp region on chromosome 11D‐E2 and whole‐exome sequence analysis identified a heterozygous mutation in the DNA polymerase gamma‐2, accessory subunit ( Polg2 ) resulting in a nonsense mutation, Tyr265Stop (Y265X), which co‐segregated with RCALC2. Kidneys of mutant mice ( Polg2 + / Y265X ) had lower POLG2 mRNA and protein expression, compared to wild‐type littermates ( Polg2 +/+ ). The Polg2 +/Y265X and Polg2 + / + mice had similar plasma concentrations of sodium, potassium, calcium, phosphate, chloride, urea, creatinine, glucose, and alkaline phosphatase activity; and similar urinary fractional excretion of calcium, phosphate, oxalate, and protein. Polg2 encodes the minor subunit of the mitochondrial DNA (mtDNA) polymerase and the mtDNA content in Polg2 + / Y265X kidneys was reduced compared to Polg2 +/+ mice, and cDNA expression profiling revealed differential expression of 26 genes involved in several biological processes including mitochondrial DNA function, apoptosis, and ubiquitination, the complement pathway, and inflammatory pathways. In addition, plasma of Polg2 + / Y265X mice, compared to Polg2 + / + littermates had higher levels of reactive oxygen species. Thus, our studies have identified a mutant mouse model for inherited renal calcification associated with a Polg2 nonsense mutation. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.

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“…following a single sample two-sided Student's t-test. AE-MS analyses were performed in triplicate using label free quantitation and compared to untagged control cells as we (Lim et al, 2018) and others have done previously using similar instrumentation and methods. Imputation was performed only on missing values in control samples and random values were drawn from a narrow distribution equivalent to the limit of detection of the instrument.…”

Section: Experimental Design and Statistical Rationalementioning

confidence: 99%

Dissecting the Roles of Mitochondrial Complex I Intermediate Assembly (MCIA) Complex Factors in the Biogenesis of Complex I

Formosa

Muellner-Wong

Reljić

et al. 2019

Preprint

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Mitochondrial Complex I harbors 7 mitochondrial and 38 nuclear-encoded subunits. Its biogenesis requires the assembly and integration of distinct intermediate modules, mediated by numerous assembly factors. The Mitochondrial Complex I Intermediate Assembly (MCIA) complex, containing assembly factors NDUFAF1, ECSIT, ACAD9, and TMEM126B, is required for building the intermediate ND2-module. The role of the MCIA complex and the involvement of other proteins in the biogenesis of this module is unclear. Cell knockout studies reveal that while each MCIA component is critical for complex I assembly, a hierarchy of stability exists centred on ACAD9. We also identify TMEM186 and COA1 as bona fide components of the MCIA complex with loss of either resulting in in MCIA complex defects and reduced complex I assembly. TMEM186 enriches with newly translated ND3, while COA1 enriches with ND2. Our findings provide new functional insights into the essential nature of the MCIA complex in complex I assembly.

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Loss of the Mitochondrial Fatty Acid β-Oxidation Protein Medium-Chain Acyl-Coenzyme A Dehydrogenase Disrupts Oxidative Phosphorylation Protein Complex Stability and Function

Cited by 49 publications

References 43 publications

Understanding the role of OXPHOS dysfunction in the pathogenesis of ECHS1 deficiency

Understanding the role of OXPHOS dysfunction in the pathogenesis of ECHS1 deficiency

An N-Ethyl-N-Nitrosourea (ENU)-Induced Tyr265Stop Mutation of the DNA Polymerase Accessory Subunit Gamma 2 (Polg2) Is Associated With Renal Calcification in Mice

Dissecting the Roles of Mitochondrial Complex I Intermediate Assembly (MCIA) Complex Factors in the Biogenesis of Complex I

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