Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease

Nsiah-Sefaa, Abena; McKenzie, Matthew

doi:10.1042/bsr20150295

Cited by 114 publications

(92 citation statements)

References 144 publications

(210 reference statements)

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“…In the case of glucose, pyruvate generated via glycolysis is next converted into acetyl‐coenzyme A (acetyl‐coA). Acetyl‐coA is further metabolized within the mitochondria matrix via the Krebs cycle (also known as the citric acid cycle or tricarboxylic acid [TCA] cycle) to yield NADH and FADH 2 , which then undergo oxidative phosphorylation via the electron transport chain to generate ATP . Mitochondrial fatty acid β‐oxidation is another critical pathway to yield energy upon uptake of free fatty acids liberated via lipolysis.…”

Section: Nlrp3 In Health and Diseasementioning

confidence: 99%

“…Mitochondrial fatty acid β‐oxidation is another critical pathway to yield energy upon uptake of free fatty acids liberated via lipolysis. Fatty acid oxidation of long chain acyl‐CoA esters, which form the backbone for phospholipid, cholesterol, and triacylglycerol synthesis, generates acetyl‐coA that is utilized by the Krebs cycle and oxidative phosphorylation to generate ATP . Interestingly, a side product of oxidative phosphorylation is the production of mtROS that can cause cellular and mitochondrial DNA (mtDNA) damage .…”

Section: Nlrp3 In Health and Diseasementioning

confidence: 99%

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Stressing out the mitochondria: Mechanistic insights into NLRP3 inflammasome activation

Yabal

Calleja

Simpson

et al. 2018

Journal of Leukocyte Biology

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Inflammasomes are multimeric protein complexes that induce the cleavage and release of bioactive IL-1 and cause a lytic form of cell death, termed pyroptosis. Due to its diverse triggers, ranging from infectious pathogens and host danger molecules to environmental irritants, the NOD-like receptor protein 3 (NLRP3) inflammasome remains the most widely studied inflammasome to date. Despite intense scrutiny, a universal mechanism for its activation remains elusive, although, recent research has focused on mitochondrial dysfunction or potassium (K + ) efflux as key events. In this review, we give a general overview of NLRP3 inflammasome activation and explore the recently emerging noncanonical and alternative pathways to NLRP3 activation. We highlight the role of the NLRP3 inflammasome in the pathogenesis of metabolic disease that is associated with mitochondrial and oxidative stress. Finally, we interrogate the mechanisms proposed to trigger NLRP3 inflammasome assembly and activation. A greater understanding of how NLRP3 inflammasome activation is triggered may reveal new therapeutic targets for the treatment of inflammatory disease. K E Y W O R D Scaspases, inflammasome, metabolism, mitochondria, reactive oxygen species Abbreviations: AIM2, absent in Melanoma; AMPK, AMP-activated protein kinase; APAF-1, apoptosis protease activating factor-1; ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain; BMDCs, bone marrow dendritic

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Section: Nlrp3 In Health and Diseasementioning

confidence: 99%

Section: Nlrp3 In Health and Diseasementioning

confidence: 99%

Stressing out the mitochondria: Mechanistic insights into NLRP3 inflammasome activation

Yabal

Calleja

Simpson

et al. 2018

Journal of Leukocyte Biology

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“…Decreased mitochondrial fatty acid oxidation (FAO) and increased lipogenesis are major contributors to lipid accumulation in liver and other tissues (3). Excessive hepatic ROS generation and decreased cellular antioxidative activity lead to oxidative stress and hepatic oxidative injury (2,4).…”

Section: Hepatic Lipid and Reactive Oxygen Species (Ros)mentioning

confidence: 99%

“…Hepatic catalase was assayed by a colormetric method using a catalase testing kit (Nanjing Jiancheng Biotech.). Mitochondrial FAO rate was determined in intact isolated mitochondria from the 14 C-labeled acid-soluble metabolites in a sealed system using [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]palmitate (GE Healthcare) as the substrate according to the method described previously (22).…”

mentioning

confidence: 99%

Specific Inhibition of Acyl-CoA Oxidase-1 by an Acetylenic Acid Improves Hepatic Lipid and Reactive Oxygen Species (ROS) Metabolism in Rats Fed a High Fat Diet

Zeng

Deng

Wang

et al. 2017

Journal of Biological Chemistry

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Edited by Dennis R. VoelkerA chronic high fat diet results in hepatic mitochondrial dysfunction and induction of peroxisomal fatty acid oxidation (FAO); whether specific inhibition of peroxisomal FAO benefits mitochondrial FAO and reactive oxygen species (ROS) metabolism remains unclear. In this study a specific inhibitor for the rate-limiting enzyme involved in peroxisomal FAO, acyl-CoA oxidase-1 (ACOX1) was developed and used for the investigation of peroxisomal FAO inhibition upon mitochondrial FAO and ROS metabolism. Specific inhibition of ACOX1 by 10,12-tricosadiynoic acid increased hepatic mitochondrial FAO via activation of the SIRT1-AMPK (adenosine 5-monophosphateactivated protein kinase) pathway and proliferator activator receptor ␣ and reduced hydrogen peroxide accumulation in high fat diet-fed rats, which significantly decreased hepatic lipid and ROS contents, reduced body weight gain, and decreased serum triglyceride and insulin levels. Inhibition of ACOX1 is a novel and effective approach for the treatment of high fat dietor obesity-induced metabolic diseases by improving mitochondrial lipid and ROS metabolism. Hepatic lipid and reactive oxygen species (ROS)2 accumulation due to hyperlipidemia and obesity are critical factors associated with the prevalence of metabolic and cardiovascular diseases (1, 2). Decreased mitochondrial fatty acid oxidation (FAO) and increased lipogenesis are major contributors to lipid accumulation in liver and other tissues (3). Excessive hepatic ROS generation and decreased cellular antioxidative activity lead to oxidative stress and hepatic oxidative injury (2, 4). Agents that are able to promote mitochondrial fatty acid oxidation or have antilipogenic and antioxidative effects will improve lipid and ROS metabolism and attenuate hepatic steatosis and oxidative injury.Peroxisomes are subcellular respiratory organelles that are critical for the metabolism of long chain and branched-chain fatty acids (5). Peroxisomes are sensitive to external signals and are easy to proliferate under conditions of high fat diet (HFD) (6, 7), diabetes (8), or hypolipidemic drug treatment (9); peroxisomal FAO is induced, oxidation capacity is increased by 2-10-fold, and peroxisomal FAO is regulated by the peroxisome proliferator activator receptor ␣ isoform (PPAR␣) (5).Acyl-CoA oxidase-1 (ACOX1, EC 1.3.3.6) is a flavoenzyme that catalyzes the initial and rate-determining reaction of the classical peroxisomal FAO using straight-chain fatty acyl-CoAs as the substrates, which donates electrons to molecular oxygen generating hydrogen peroxide; this byproduct is further decomposed by catalase, as shown in Fig. 1. The classical peroxisomal FAO has been known for nearly 40 years (9), but it is still not clear about the exact role of peroxisomal FAO in cellular fatty acid metabolism and especially its effect on mitochondrial fatty acid oxidation. Several lines of evidence have shown that chronic induction of peroxisomal FAO may cause oxidative stress and is potentially detrimental to mitochondrial fa...

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“…Representative examples include methylmalonic and propionic acidurias [de Keyzer et al, 2009;Baruteau et al, 2014], fatty acid oxidation disorders [Nsiah-Sefaa and McKenzie, 2016], disorders of purine/pyrimidine synthesis [Duley et al, 2011], urea cycle disorders such as argininosuccinic aciduria due to lyase deficiency [Monné et al, 2015], and many others. The importance of distinguishing between PMD and the primary cause of the clinical phenotype with or without SMD is emphasized by a clinical example of the following patient in our practice.…”

Section: Inborn Errors Of Metabolismmentioning

confidence: 99%

Primary Mitochondrial Disease and Secondary Mitochondrial Dysfunction: Importance of Distinction for Diagnosis and Treatment

2016

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Mitochondrial disease refers to a heterogeneous group of disorders resulting in defective cellular energy production due to abnormal oxidative phosphorylation (oxphos). Primary mitochondrial disease (PMD) is diagnosed clinically and ideally, but not always, confirmed by a known or indisputably pathogenic mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) mutation. The PMD genes either encode oxphos proteins directly or they affect oxphos function by impacting production of the complex machinery needed to run the oxphos process. However, many disorders have the ‘mitochondrial' phenotype without an identifiable mtDNA or nDNA mutation or they have a variant of unknown clinical significance. Secondary mitochondrial dysfunction (SMD) can be caused by genes encoding neither function nor production of the oxphos proteins and accompanies many hereditary non-mitochondrial diseases. SMD may also be due to nongenetic causes such as environmental factors. In our practice, we see many patients with clinical signs of mitochondrial dysfunction based on phenotype, biomarkers, imaging, muscle biopsy, or negative/equivocal mtDNA or nDNA test results. In these cases, it is often tempting to assign a patient's phenotype to ‘mitochondrial disease', but SMD is often challenging to distinguish from PMD. Fortunately, rapid advances in molecular testing, made possible by next generation sequencing, have been effective at least in some cases in establishing accurate diagnoses to distinguish between PMD and SMD. This is important, since their treatments and prognoses can be quite different. However, even in the absence of the ability to distinguish between PMD and SMD, treating SMD with standard treatments for PMD can be effective. We review the latest findings regarding mitochondrial disease/dysfunction and give representative examples in which differentiation between PMD and SMD has been crucial for diagnosis and treatment.

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Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease

Cited by 114 publications

References 144 publications

Stressing out the mitochondria: Mechanistic insights into NLRP3 inflammasome activation

Stressing out the mitochondria: Mechanistic insights into NLRP3 inflammasome activation

Specific Inhibition of Acyl-CoA Oxidase-1 by an Acetylenic Acid Improves Hepatic Lipid and Reactive Oxygen Species (ROS) Metabolism in Rats Fed a High Fat Diet

Primary Mitochondrial Disease and Secondary Mitochondrial Dysfunction: Importance of Distinction for Diagnosis and Treatment

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