Publications by authors named "Placido Navas"

166 Publications

Cooperation between CYB5R3 and NOX4 via coenzyme Q mitigates endothelial inflammation.

Redox Biol 2021 Oct 14;47:102166. Epub 2021 Oct 14.

Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA; Center for Microvascular Research, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address:

NADPH oxidase 4 (NOX4) regulates endothelial inflammation by producing hydrogen peroxide (HO) and to a lesser extent O. The ratio of NOX4-derived HO and O can be altered by coenzyme Q (CoQ) mimics. Therefore, we hypothesize that cytochrome b5 reductase 3 (CYB5R3), a CoQ reductase abundant in vascular endothelial cells, regulates inflammatory activation. To examine endothelial CYB5R3 in vivo, we created tamoxifen-inducible endothelium-specific Cyb5r3 knockout mice (R3 KO). Radiotelemetry measurements of systolic blood pressure showed systemic hypotension in lipopolysaccharides (LPS) challenged mice, which was exacerbated in R3 KO mice. Meanwhile, LPS treatment caused greater endothelial dysfunction in R3 KO mice, evaluated by acetylcholine-induced vasodilation in the isolated aorta, accompanied by elevated mRNA expression of vascular adhesion molecule 1 (Vcam-1). Similarly, in cultured human aortic endothelial cells (HAEC), LPS and tumor necrosis factor α (TNF-α) induced VCAM-1 protein expression was enhanced by Cyb5r3 siRNA, which was ablated by silencing the Nox4 gene simultaneously. Moreover, super-resolution confocal microscopy indicated mitochondrial co-localization of CYB5R3 and NOX4 in HAECs. APEX2-based electron microscopy and proximity biotinylation also demonstrated CYB5R3's localization on the mitochondrial outer membrane and its interaction with NOX4, which was further confirmed by the proximity ligation assay. Notably, Cyb5r3 knockdown HAECs showed less total HO but more mitochondrial O. Using inactive or non-membrane bound active CYB5R3, we found that CYB5R3 activity and membrane translocation are needed for optimal generation of HO by NOX4. Lastly, cells lacking the CoQ synthesizing enzyme COQ6 showed decreased NOX4-derived HO, indicating a requirement for endogenous CoQ in NOX4 activity. In conclusion, CYB5R3 mitigates endothelial inflammatory activation by assisting in NOX4-dependent HO generation via CoQ.
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http://dx.doi.org/10.1016/j.redox.2021.102166DOI Listing
October 2021

Cellular Models for Primary CoQ Deficiency Pathogenesis Study.

Int J Mol Sci 2021 Sep 22;22(19). Epub 2021 Sep 22.

Centro Andaluz de Biología del Desarrollo, and CIBERER, Instituto de Salud Carlos III, Universidad Pablo de Olavide-CSIC-JA, Carretera de Utrera km1, 41013 Sevilla, Spain.

Primary coenzyme Q (CoQ) deficiency includes a heterogeneous group of mitochondrial diseases characterized by low mitochondrial levels of CoQ due to decreased endogenous biosynthesis rate. These diseases respond to CoQ treatment mainly at the early stages of the disease. The advances in the next generation sequencing (NGS) as whole-exome sequencing (WES) and whole-genome sequencing (WGS) have increased the discoveries of mutations in either gene already described to participate in CoQ biosynthesis or new genes also involved in this pathway. However, these technologies usually provide many mutations in genes whose pathogenic effect must be validated. To functionally validate the impact of gene variations in the disease's onset and progression, different cell models are commonly used. We review here the use of yeast strains for functional complementation of human genes, dermal skin fibroblasts from patients as an excellent tool to demonstrate the biochemical and genetic mechanisms of these diseases and the development of human-induced pluripotent stem cells (hiPSCs) and iPSC-derived organoids for the study of the pathogenesis and treatment approaches.
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http://dx.doi.org/10.3390/ijms221910211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8508219PMC
September 2021

Secondary CoQ deficiency, bioenergetics unbalance in disease and aging.

Biofactors 2021 Jul 20;47(4):551-569. Epub 2021 Apr 20.

Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain.

Coenzyme Q (CoQ ) deficiency is a rare disease characterized by a decreased accumulation of CoQ in cell membranes. Considering that CoQ synthesis and most of its functions are carried out in mitochondria, CoQ deficiency cases are usually considered a mitochondrial disease. A relevant feature of CoQ deficiency is that it is the only mitochondrial disease with a successful therapy available, the CoQ supplementation. Defects in components of the synthesis machinery caused by mutations in COQ genes generate the primary deficiency of CoQ . Mutations in genes that are not directly related to the synthesis machinery cause secondary deficiency. Cases of CoQ deficiency without genetic origin are also considered a secondary deficiency. Both types of deficiency can lead to similar clinical manifestations, but the knowledge about primary deficiency is deeper than secondary. However, secondary deficiency cases may be underestimated since many of their clinical manifestations are shared with other pathologies. This review shows the current state of secondary CoQ deficiency, which could be even more relevant than primary deficiency for clinical activity. The analysis covers the fundamental features of CoQ deficiency, which are necessary to understand the biological and clinical differences between primary and secondary CoQ deficiencies. Further, a more in-depth analysis of CoQ secondary deficiency was undertaken to consider its origins, introduce a new way of classification, and include aging as a form of secondary deficiency.
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http://dx.doi.org/10.1002/biof.1733DOI Listing
July 2021

Editorial: "Mitochondrial coenzyme Q homeostasis: Signalling, respiratory chain stability and diseases."

Free Radic Biol Med 2021 06 9;169:12-13. Epub 2021 Apr 9.

Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, G12 8QQ, Glasgow, United Kingdom. Electronic address:

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http://dx.doi.org/10.1016/j.freeradbiomed.2021.04.005DOI Listing
June 2021

Regulation of coenzyme Q biosynthesis pathway in eukaryotes.

Free Radic Biol Med 2021 03 4;165:312-323. Epub 2021 Feb 4.

Centro Andaluz de Biología del Desarrollo and CIBERER, Instituto de Salud Carlos III, Universidad Pablo de Olavide-CSIC-JA, Sevilla, 41013, Spain. Electronic address:

Coenzyme Q (CoQ, ubiquinone/ubiquinol) is a ubiquitous and unique molecule that drives electrons in mitochondrial respiratory chain and an obligatory step for multiple metabolic pathways in aerobic metabolism. Alteration of CoQ biosynthesis or its redox stage are causing mitochondrial dysfunctions as hallmark of heterogeneous disorders as mitochondrial/metabolic, cardiovascular, and age-associated diseases. Regulation of CoQ biosynthesis pathway is demonstrated to affect all steps of proteins production of this pathway, posttranslational modifications and protein-protein-lipid interactions inside mitochondria. There is a bi-directional relationship between CoQ and the epigenome in which not only the CoQ status determines the epigenetic regulation of many genes, but CoQ biosynthesis is also a target for epigenetic regulation, which adds another layer of complexity to the many pathways by which CoQ levels are regulated by environmental and developmental signals to fulfill its functions in eukaryotic aerobic metabolism.
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http://dx.doi.org/10.1016/j.freeradbiomed.2021.01.055DOI Listing
March 2021

NQO1 protects obese mice through improvements in glucose and lipid metabolism.

NPJ Aging Mech Dis 2020 Nov 19;6(1):13. Epub 2020 Nov 19.

Translational Gerontology Branch, National Institute on Aging Intramural Program, National Institutes of Health, Baltimore, MD, 21224, USA.

Chronic nutrient excess leads to metabolic disorders and insulin resistance. Activation of stress-responsive pathways via Nrf2 activation contributes to energy metabolism regulation. Here, inducible activation of Nrf2 in mice and transgenesis of the Nrf2 target, NQO1, conferred protection from diet-induced metabolic defects through preservation of glucose homeostasis, insulin sensitivity, and lipid handling with improved physiological outcomes. NQO1-RNA interaction mediated the association with and inhibition of the translational machinery in skeletal muscle of NQO1 transgenic mice. NQO1-Tg mice on high-fat diet had lower adipose tissue macrophages and enhanced expression of lipogenic enzymes coincident with reduction in circulating and hepatic lipids. Metabolomics data revealed a systemic metabolic signature of improved glucose handling, cellular redox, and NAD metabolism while label-free quantitative mass spectrometry in skeletal muscle uncovered a distinct diet- and genotype-dependent acetylation pattern of SIRT3 targets across the core of intermediary metabolism. Thus, under nutritional excess, NQO1 transgenesis preserves healthful benefits.
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http://dx.doi.org/10.1038/s41514-020-00051-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678866PMC
November 2020

Age-related mitochondrial dysfunction as a key factor in COVID-19 disease.

Exp Gerontol 2020 12 7;142:111147. Epub 2020 Nov 7.

Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC, CIBERER, Instituto de Salud Carlos III, 41013 Sevilla, Spain. Electronic address:

SARS-CoV-2 causes a severe pneumonia (COVID-19) that affects essentially elderly people. In COVID-19, macrophage infiltration into the lung causes a rapid and intense cytokine storm leading finally to a multi-organ failure and death. Comorbidities such as metabolic syndrome, obesity, type 2 diabetes, lung and cardiovascular diseases, all of them age-associated diseases, increase the severity and lethality of COVID-19. Mitochondrial dysfunction is one of the hallmarks of aging and COVID-19 risk factors. Dysfunctional mitochondria is associated with defective immunological response to viral infections and chronic inflammation. This review discuss how mitochondrial dysfunction is associated with defective immune response in aging and different age-related diseases, and with many of the comorbidities associated with poor prognosis in the progression of COVID-19. We suggest here that chronic inflammation caused by mitochondrial dysfunction is responsible of the explosive release of inflammatory cytokines causing severe pneumonia, multi-organ failure and finally death in COVID-19 patients. Preventive treatments based on therapies improving mitochondrial turnover, dynamics and activity would be essential to protect against COVID-19 severity.
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http://dx.doi.org/10.1016/j.exger.2020.111147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648491PMC
December 2020

Coenzyme Q Treatment Monitoring in Different Human Biological Samples.

Antioxidants (Basel) 2020 Oct 13;9(10). Epub 2020 Oct 13.

Clinical Biochemistry Department, Institut de Recerca Sant Joan de Déu, Passeig Sant Joan de Déu, 2, 08950 Esplugues de Llobregat, Barcelona, Spain.

Coenzyme Q (CoQ) treatment monitoring is a matter of debate since CoQ distribution from plasma to blood cells and tissues is not fully understood. We aimed to analyze the CoQ levels in a wide set of human biological samples (plasma, blood mononuclear cells (BMCs), platelets, urinary cells, and skeletal muscle) from a group of 11 healthy male runners before and after CoQ supplementation. The CoQ content in the different samples was analyzed by HPLC coupled to electrochemical detection. No significant differences were observed in the CoQ levels measured in the BMCs, platelets, and urine after the one-month treatment period. Plasma CoQ (expressed in absolute values and values relative to total cholesterol) significantly increased after CoQ supplementation ( = 0.003 in both cases), and the increase in CoQ in muscle approached significance ( = 0.074). CoQ levels were increased in the plasma of all supplemented subjects, and muscle CoQ levels were increased in 8 out of 10 supplemented subjects. In conclusion, the analysis of CoQ in plasma samples seems to be the best surrogate biomarker for CoQ treatment monitoring. Moreover, oral CoQ administration was effective for increasing muscle CoQ concentrations in most subjects.
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http://dx.doi.org/10.3390/antiox9100979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601005PMC
October 2020

Na controls hypoxic signalling by the mitochondrial respiratory chain.

Nature 2020 10 29;586(7828):287-291. Epub 2020 Jul 29.

Unidad de Investigación, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Princesa (IIS-IP), Madrid, Spain.

All metazoans depend on the consumption of O by the mitochondrial oxidative phosphorylation system (OXPHOS) to produce energy. In addition, the OXPHOS uses O to produce reactive oxygen species that can drive cell adaptations, a phenomenon that occurs in hypoxia and whose precise mechanism remains unknown. Ca is the best known ion that acts as a second messenger, yet the role ascribed to Na is to serve as a mere mediator of membrane potential. Here we show that Na acts as a second messenger that regulates OXPHOS function and the production of reactive oxygen species by modulating the fluidity of the inner mitochondrial membrane. A conformational shift in mitochondrial complex I during acute hypoxia drives acidification of the matrix and the release of free Ca from calcium phosphate (CaP) precipitates. The concomitant activation of the mitochondrial Na/Ca exchanger promotes the import of Na into the matrix. Na interacts with phospholipids, reducing inner mitochondrial membrane fluidity and the mobility of free ubiquinone between complex II and complex III, but not inside supercomplexes. As a consequence, superoxide is produced at complex III. The inhibition of Na import through the Na/Ca exchanger is sufficient to block this pathway, preventing adaptation to hypoxia. These results reveal that Na controls OXPHOS function and redox signalling through an unexpected interaction with phospholipids, with profound consequences for cellular metabolism.
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http://dx.doi.org/10.1038/s41586-020-2551-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992277PMC
October 2020

High coenzyme Q10 plasma levels improve stress and damage markers in professional soccer players during competition.

Int J Vitam Nutr Res 2020 Jul 8:1-12. Epub 2020 Jul 8.

Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, and CIBERER, Instituto de Salud Carlos III, Sevilla, Spain.

Ubiquinol, the reduced form of Coenzyme Q (CoQ), is a key factor in bioenergetics and antioxidant protection. During competition, professional soccer players suffer from considerable physical stress causing high risk of muscle damage. For athletes, supplementation with several antioxidants, including CoQ, is widely recommended to avoid oxidative stress and muscle damage. We performed an observational study of plasma parameters associated with CoQ levels in professional soccer players of the Spanish First League team Athletic Club de Bilbao over two consecutive seasons (n = 24-25) in order determine their relationship with damage, stress and performance during competition. We analyzed three different moments of the competition: preterm, initial phase and mid phase. Metabolites and factors related with stress (testosterone/cortisol) and muscle damage (creatine kinase) were determined. Physical activity during matches was analyzed over the 2015/16 season in those players participating in complete matches. In the mid phase of competition, CoQ levels were higher in 2015/16 (906.8 ± 307.9 vs. 584.3 ± 196.3 pmol/mL, p = 0.0006) High levels of CoQ in the hardest phase of competition were associated with a reduction in the levels of the muscle-damage marker creatine kinase (Pearsons' correlation coefficient (r) = - 0.460, p = 0.00168) and a trend for the stress marker cortisol (r = -0.252, p = 0.150). Plasma ubiquinol was also associated with better kidney function (r = -0.287, p = 0.0443 for uric acid). Furthermore, high CoQ levels were associated with higher muscle performance during matches. Our results suggest that high levels of plasma CoQ can prevent muscle damage, improve kidney function and are associated with higher performance in professional soccer players during competition.
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http://dx.doi.org/10.1024/0300-9831/a000659DOI Listing
July 2020

Protective effect of maternal exercise against amyloid-β neurotoxicity in the male rat offspring's cerebellum.

J Dev Orig Health Dis 2020 10 23;11(5):521-532. Epub 2020 Jun 23.

Programa de Pós-Graduação em Ciências Biológicas - Bioquímica, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.

The Developmental Origins of Health and Disease (DOHaD) states that intrauterine maternal environment influences postnatal life by programming offspring's metabolism. Intrauterine milieu induced by exercise during pregnancy promotes long-lasting benefits to the offspring's health and seems to offer some resistance against chronic diseases in adult life. Alzheimer's disease is a public health concern with limited treatment options. In the present study, we assessed the potential of maternal exercise during pregnancy in long-term programming of young adult male rat offspring's cerebellar metabolism in conferring neuroprotection against amyloid-β (Aβ) neurotoxicity. Female Wistar rats were submitted to a swimming protocol 1 week prior mating and throughout pregnancy (five sessions/a week lasting 30 min). Aβ oligomers were infused bilaterally in the brain ventricles of 60-day-old male offspring. Fourteen days after surgery, we measured parameters related to redox state, mitochondrial function, and the immunocontent of proteins related to synaptic function. We found that maternal exercise during pregnancy attenuated several parameters in the offspring's male rat cerebellum, such as the reactive species rise, the increase of inducible nitric oxide synthase immunocontent and tau phosphorylation induced by Aβ oligomers, increased mitochondrial fission indicated by dynamin-related protein 1 (DRP1), and protein oxidation identified by carbonylation. Strikingly, we find that maternal exercise promotes changes in the rat offspring's cerebellum that are still evident in young adult life. These favorable neurochemical changes in offspring's cerebellum induced by maternal exercise may contribute to a protective phenotype against Aβ-induced neurotoxicity in young adult male rat offspring.
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http://dx.doi.org/10.1017/S2040174420000562DOI Listing
October 2020

Resveratrol Regulates the Expression of Genes Involved in CoQ Synthesis in Liver in Mice Fed with High Fat Diet.

Antioxidants (Basel) 2020 May 15;9(5). Epub 2020 May 15.

Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, and CIBERER, Instituto de Salud Carlos III, 41013 Sevilla, Spain.

Resveratrol (RSV) is a bioactive natural molecule that induces antioxidant activity and increases protection against oxidative damage. RSV could be used to mitigate damages associated to metabolic diseases and aging. Particularly, RSV regulates different aspects of mitochondrial metabolism. However, no information is available about the effects of RSV on Coenzyme Q (CoQ), a central component in the mitochondrial electron transport chain. Here, we report for the first time that RSV modulates genes and parameters associated to metabolic syndrome in mice. Mice fed with high fat diet (HFD) presented a higher weight gain, triglycerides (TGs) and cholesterol levels while RSV reverted TGs to control level but not weight or cholesterol. HFD induced a decrease of gene mRNA level, whereas RSV reversed this decrease in most of the genes. However, RSV did not show effect on CoQ, CoQ and total CoQ levels, neither in CoQ-dependent antioxidant enzymes. HFD influenced mitochondrial dynamics and mitophagy markers. RSV modulated the levels of PINK1 and PARKIN and their ratio, indicating modulation of mitophagy. In summary, we report that RSV influences some of the metabolic adaptations of HFD affecting mitochondrial physiology while also regulates gene expression levels in a process that can be associated with mitochondrial dynamics and turnover.
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http://dx.doi.org/10.3390/antiox9050431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278683PMC
May 2020

Design of High-Throughput Screening of Natural Extracts to Identify Molecules Bypassing Primary Coenzyme Q Deficiency in .

SLAS Discov 2020 03 21;25(3):299-309. Epub 2019 Nov 21.

Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide, Sevilla, Spain.

Coenzyme Q (CoQ) deficiency syndrome is a rare disease included in the family of mitochondrial diseases, which is a heterogeneous group of genetic disorders characterized by defective energy production. CoQ biosynthesis in humans requires at least 11 gene products acting in a multiprotein complex within mitochondria. The high-throughput screening (HTS) method based on the stabilization of the CoQ biosynthesis complex (Q-synthome) produced by the gene overexpression is proven here to be a successful method for identifying new molecules from natural extracts that are able to bypass the CoQ deficiency in yeast mutant cells. The main features of the new approach are the combination of two yeast targets defective in genes with different functions on CoQ biosynthesis to secure the versatility of the molecule identified, the use of glycerol as a nonfermentable carbon source providing a wide growth window, and the stringent conditions required to mark an extract as positive. The application of this pilot approach to a representative subset of 1200 samples of the Library of Natural Products of Fundación MEDINA resulted in the finding of nine positive extracts. The fractionation of three of the nine extracts allowed the identification of five molecules; two of them are present in molecule databases of natural extracts and three are nondescribed molecules. The use of this screening method opens the possibility of discovering molecules with CoQ-bypassing action useful as therapeutic agents to fight against mitochondrial diseases in human patients.
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http://dx.doi.org/10.1177/2472555219877185DOI Listing
March 2020

Haploinsufficiency Reduces Mitochondrial Lipid Oxidation and Causes Myopathy Associated with CoQ Deficiency.

J Clin Med 2019 Sep 2;8(9). Epub 2019 Sep 2.

Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, 41013 Sevilla, Spain.

Fatty acids and glucose are the main bioenergetic substrates in mammals. Impairment of mitochondrial fatty acid oxidation causes mitochondrial myopathy leading to decreased physical performance. Here, we report that haploinsufficiency of , a member of the aarF domain-containing mitochondrial protein kinase family, in human is associated with liver dysfunction and severe mitochondrial myopathy with lipid droplets in skeletal muscle. In order to better understand the etiology of this rare disorder, we generated a heterozygous knockout mouse model to perform in vivo and cellular studies using integrated analysis of physiological and omics data (transcriptomics-metabolomics). The data showed that +/- mice exhibited impaired fatty acid oxidation, liver dysfunction, and mitochondrial myopathy in skeletal muscle resulting in lower physical performance. Significant decrease in Coenzyme Q (CoQ) biosynthesis was observed and supplementation with CoQ partially rescued the phenotype both in the human subject and mouse model. These results indicate that ADCK2 is involved in organismal fatty acid metabolism and in CoQ biosynthesis in skeletal muscle. We propose that patients with isolated myopathies and myopathies involving lipid accumulation be tested for possible defect as they are likely to be responsive to CoQ supplementation.
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http://dx.doi.org/10.3390/jcm8091374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6780728PMC
September 2019

Vanillic Acid Restores Coenzyme Q Biosynthesis and ATP Production in Human Cells Lacking .

Oxid Med Cell Longev 2019 10;2019:3904905. Epub 2019 Jul 10.

Clinical Genetics Unit, Department of Women's and Children's Health, University of Padova, Italy.

Coenzyme Q (CoQ), a redox-active lipid, is comprised of a quinone group and a polyisoprenoid tail. It is an electron carrier in the mitochondrial respiratory chain, a cofactor of other mitochondrial dehydrogenases, and an essential antioxidant. CoQ requires a large set of enzymes for its biosynthesis; mutations in genes encoding these proteins cause primary CoQ deficiency, a clinically and genetically heterogeneous group of diseases. Patients with CoQ deficiency often respond to oral CoQ supplementation. Treatment is however problematic because of the low bioavailability of CoQ and the poor tissue delivery. In recent years, bypass therapy using analogues of the precursor of the aromatic ring of CoQ has been proposed as a promising alternative. We have previously shown using a yeast model that vanillic acid (VA) can bypass mutations of , a monooxygenase required for the hydroxylation of the C5 carbon of the ring. In this work, we have generated a human cell line lacking functional using CRISPR/Cas9 technology. We show that these cells cannot synthesize CoQ and display severe ATP deficiency. Treatment with VA can recover CoQ biosynthesis and ATP production. Moreover, these cells display increased ROS production, which is only partially corrected by exogenous CoQ, while VA restores ROS to normal levels. Furthermore, we show that these cells accumulate 3-decaprenyl-1,4-benzoquinone, suggesting that in mammals, the decarboxylation and C1 hydroxylation reactions occur before or independently of the C5 hydroxylation. Finally, we show that isoform c (transcript NM_182480) does not encode an active enzyme. VA can be produced in the liver by the oxidation of vanillin, a nontoxic compound commonly used as a food additive, and crosses the blood-brain barrier. These characteristics make it a promising compound for the treatment of patients with CoQ deficiency due to mutations.
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http://dx.doi.org/10.1155/2019/3904905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6652073PMC
January 2020

Clinical presentation and proteomic signature of patients with TANGO2 mutations.

J Inherit Metab Dis 2020 03 13;43(2):297-308. Epub 2019 Aug 13.

Secció d'Errors Congènits del Metabolisme - IBC, Servei de Bioquímica I Genètìca Molecular, Hospital Clínìc, IDIBAPS, CIBERER, Barcelona, Spain.

Transport And Golgi Organization protein 2 (TANGO2) deficiency has recently been identified as a rare metabolic disorder with a distinct clinical and biochemical phenotype of recurrent metabolic crises, hypoglycemia, lactic acidosis, rhabdomyolysis, arrhythmias, and encephalopathy with cognitive decline. We report nine subjects from seven independent families, and we studied muscle histology, respiratory chain enzyme activities in skeletal muscle and proteomic signature of fibroblasts. All nine subjects carried autosomal recessive TANGO2 mutations. Two carried the reported deletion of exons 3 to 9, one homozygous, one heterozygous with a 22q11.21 microdeletion inherited in trans. The other subjects carried three novel homozygous (c.262C>T/p.Arg88*; c.220A>C/p.Thr74Pro; c.380+1G>A), and two further novel heterozygous (c.6_9del/p.Phe6del); c.11-13delTCT/p.Phe5del mutations. Immunoblot analysis detected a significant decrease of TANGO2 protein. Muscle histology showed mild variation of fiber diameter, no ragged-red/cytochrome c oxidase-negative fibers and a defect of multiple respiratory chain enzymes and coenzyme Q (CoQ ) in two cases, suggesting a possible secondary defect of oxidative phosphorylation. Proteomic analysis in fibroblasts revealed significant changes in components of the mitochondrial fatty acid oxidation, plasma membrane, endoplasmic reticulum-Golgi network and secretory pathways. Clinical presentation of TANGO2 mutations is homogeneous and clinically recognizable. The hemizygous mutations in two patients suggest that some mutations leading to allele loss are difficult to detect. A combined defect of the respiratory chain enzymes and CoQ with altered levels of several membrane proteins provides molecular insights into the underlying pathophysiology and may guide rational new therapeutic interventions.
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http://dx.doi.org/10.1002/jimd.12156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078914PMC
March 2020

Cardiotrophin-1 is an anti-inflammatory cytokine and promotes IL-4-induced M2 macrophage polarization.

FASEB J 2019 06 20;33(6):7578-7587. Epub 2019 Mar 20.

Institute of Biomedicine of Seville (IBiS), Consejo Superior de Investigaciones Científicas (CSIC)-University of Seville-Virgen del Rocio University Hospital, Seville, Spain.

Macrophages play a central role in tissue remodeling, repair, and resolution of inflammation. Macrophage polarization to M1 or M2 activation status may determine the progression or resolution of the inflammatory response. We have previously reported that cardiotrophin-1 (CT-1) displays both cytoprotective and metabolic activities. The role of CT-1 in inflammation remains poorly understood. Here, we employed recombinant CT-1 (rCT-1) and used -null mice and myeloid-specific transgenic mice to investigate whether CT-1 might play a role in the modulation of the inflammatory response. We observed that deficiency was associated with enhanced release of inflammatory mediators and with stronger activation of NF-κB in response to LPS, whereas the inflammatory response was attenuated in transgenic mice or by administering rCT-1 to wild-type animals prior to LPS challenge. We found that CT-1 promoted IL-6 expression only by nonhematopoietic cells, whereas LPS up-regulated IL-6 expression in both hematopoietic and nonhematopoietic cells. Notably, rCT-1 inhibited LPS-mediated soluble IL-6R induction. Using mice, we showed that rCT-1 inhibited LPS-induced TNF-α and IFN-γ response in an IL-6-independent manner. Importantly, we demonstrated that CT-1 primes macrophages for IL-4-dependent M2 polarization by inducing IL-4 receptor expression. Mechanistic analyses showed that the signal transducer and activator of transcription 3-suppressor of cytokine signaling 3 axis mediates this effect. Our findings support the notion that CT-1 is a critical regulator of inflammation and suggest that rCT-1 could be a molecule with potential therapeutic application in inflammatory conditions.-Carneros, D., Santamaría, E. M., Larequi, E., Vélez-Ortiz, J. M., Reboredo, M., Mancheño, U., Perugorria, M. J., Navas, P., Romero-Gómez, M., Prieto, J., Hervás-Stubbs, S., Bustos, M. Cardiotrophin-1 is an anti-inflammatory cytokine and promotes IL-4-induced M2 macrophage polarization.
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http://dx.doi.org/10.1096/fj.201801563RDOI Listing
June 2019

Plasma coenzyme Q status is impaired in selected genetic conditions.

Sci Rep 2019 01 28;9(1):793. Epub 2019 Jan 28.

Inborn errors of metabolism Unit, Institut de Recerca Sant Joan de Déu, Barcelona, Spain.

Identifying diseases displaying chronic low plasma Coenzyme Q (CoQ) values may be important to prevent possible cardiovascular dysfunction. The aim of this study was to retrospectively evaluate plasma CoQ concentrations in a large cohort of pediatric and young adult patients. We evaluated plasma CoQ values in 597 individuals (age range 1 month to 43 years, average 11 years), studied during the period 2005-2016. Patients were classified into 6 different groups: control group of healthy participants, phenylketonuric patients (PKU), patients with mucopolysaccharidoses (MPS), patients with other inborn errors of metabolism (IEM), patients with neurogenetic diseases, and individuals with neurological diseases with no genetic diagnosis. Plasma total CoQ was measured by reverse-phase high-performance liquid chromatography with electrochemical detection and ultraviolet detection at 275 nm. ANOVA with Bonferroni correction showed that plasma CoQ values were significantly lower in the PKU and MPS groups than in controls and neurological patients. The IEM group showed intermediate values that were not significantly different from those of the controls. In PKU patients, the Chi-Square test showed a significant association between having low plasma CoQ values and being classic PKU patients. The percentage of neurogenetic and other neurological patients with low CoQ values was low (below 8%). In conclusión, plasma CoQ monitoring in selected groups of patients with different IEM (especially in PKU and MPS patients, but also in IEM under protein-restricted diets) seems advisable to prevent the possibility of a chronic blood CoQ suboptimal status in such groups of patients.
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http://dx.doi.org/10.1038/s41598-018-37542-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349877PMC
January 2019

Muscle Involvement in a Large Cohort of Pediatric Patients with Genetic Diagnosis of Mitochondrial Disease.

J Clin Med 2019 Jan 10;8(1). Epub 2019 Jan 10.

Clinical Biochemistry, Pathology, Paediatric Neurology and Molecular Medicine Departments and Biobank, Institut de Recerca Sant Joan de Déu and CIBERER-ISCIII, 08950 Esplugues, Spain.

Mitochondrial diseases (MD) are a group of genetic and acquired disorders which present significant diagnostic challenges. Here we report the disease characteristics of a large cohort of pediatric MD patients ( = 95) with a definitive genetic diagnosis, giving special emphasis on clinical muscle involvement, biochemical and histopathological features. Of the whole cohort, 51 patients harbored mutations in nuclear DNA (nDNA) genes and 44 patients had mutations in mitochondrial DNA (mtDNA) genes. The nDNA patients were more likely to have a reduction in muscle fiber succinate dehydrogenase (SDH) stains and in SDH-positive blood vessels, while a higher frequency of mtDNA patients had ragged red (RRF) and blue fibers. The presence of positive histopathological features was associated with ophthalmoplegia, myopathic facies, weakness and exercise intolerance. In 17 patients younger than two years of age, RRF and blue fibers were observed only in one case, six cases presented cytochrome c oxidase (COX) reduction/COX-fibers, SDH reduction was observed in five and all except one presented SDH-positive blood vessels. In conclusion, muscle involvement was a frequent finding in our series of MD patients, especially in those harboring mutations in mtDNA genes.
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http://dx.doi.org/10.3390/jcm8010068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6352184PMC
January 2019

PARL deficiency in mouse causes Complex III defects, coenzyme Q depletion, and Leigh-like syndrome.

Proc Natl Acad Sci U S A 2019 01 21;116(1):277-286. Epub 2018 Dec 21.

VIB Center for Brain and Disease Research, 3000 Leuven, Belgium;

The mitochondrial intramembrane rhomboid protease PARL has been implicated in diverse functions in vitro, but its physiological role in vivo remains unclear. Here we show that ablation in mouse causes a necrotizing encephalomyelopathy similar to Leigh syndrome, a mitochondrial disease characterized by disrupted energy production. Mice with conditional PARL deficiency in the nervous system, but not in muscle, develop a similar phenotype as germline KOs, demonstrating the vital role of PARL in neurological homeostasis. Genetic modification of two major PARL substrates, PINK1 and PGAM5, do not modify this severe neurological phenotype. brain mitochondria are affected by progressive ultrastructural changes and by defects in Complex III (CIII) activity, coenzyme Q (CoQ) biosynthesis, and mitochondrial calcium metabolism. PARL is necessary for the stable expression of TTC19, which is required for CIII activity, and of COQ4, which is essential in CoQ biosynthesis. Thus, PARL plays a previously overlooked constitutive role in the maintenance of the respiratory chain in the nervous system, and its deficiency causes progressive mitochondrial dysfunction and structural abnormalities leading to neuronal necrosis and Leigh-like syndrome.
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http://dx.doi.org/10.1073/pnas.1811938116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6320509PMC
January 2019

Cellular and Molecular Mechanisms of Recessive Hereditary Methaemoglobinaemia Type II.

J Clin Med 2018 Oct 10;7(10). Epub 2018 Oct 10.

Centro Andaluz de Biología del Desarrollo, Departamento de Anatomía, Fisiología y Biología Celular, Universidad Pablo de Olavide-CSIC, 41013 Sevilla, Spain.

Cytochrome b5 reductase 3 (CYB5R3) is a membrane-bound NADH-dependent redox enzyme anchored to the mitochondrial outer membrane, endoplasmic reticulum, and plasma membrane. Recessive hereditary methaemoglobinaemia (RHM) type II is caused by CYB5R3 deficiency and is an incurable disease characterized by severe encephalopathy with mental retardation, microcephaly, generalized dystonia, and movement disorders. Currently, the etiology of type II RHM is poorly understood and there is no treatment for encephalopathy associated with this disease. Defective CYB5R3 leads to defects in the elongation and desaturation of fatty acids and cholesterol biosynthesis, which are conventionally linked with neurological disorders of type II RHM. Nevertheless, this abnormal lipid metabolism cannot explain all manifestations observed in patients. Current molecular and cellular studies indicate that CYB5R3 deficiency has pleiotropic tissue effects. Its localization in lipid rafts of neurons indicates its role in interneuronal contacts and its presence in caveolae of the vascular endothelial membrane suggests a role in the modulation of nitric oxide diffusion. Its role in aerobic metabolism and oxidative stress in fibroblasts, neurons, and cardiomyocytes has been reported to be due to its ability to modulate the intracellular ratio of NAD⁺/NADH. Based on the new molecular and cellular functions discovered for CYB5R3 linked to the plasma membrane and mitochondria, the conventional conception that the cause of type II RHM is a lipid metabolism disorder should be revised. We hypothesized that neurological symptoms of the disease could be caused by disorders in the synapse, aerobic metabolism, and/or vascular homeostasis rather than in disturbances of lipid metabolism.
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http://dx.doi.org/10.3390/jcm7100341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6210646PMC
October 2018

The mitochondrial phosphatase PPTC7 orchestrates mitochondrial metabolism regulating coenzyme Q biosynthesis.

Biochim Biophys Acta Bioenerg 2018 11 26;1859(11):1235-1248. Epub 2018 Sep 26.

Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA, and CIBERER Instituto de Salud Carlos III, 41013 Sevilla, Spain. Electronic address:

Coenzyme Q (CoQ) is a redox molecule critical for the proper function of energy metabolism and antioxidant defenses. Despite its essential role in cellular metabolism, the regulation of CoQ biosynthesis in humans remains mostly unknown. Herein, we determined that PPTC7 is a regulatory protein of CoQ biosynthesis required for human cell survival. We demonstrated by in vitro approaches that PPTC7 is a bona fide protein phosphatase that dephosphorylates the human COQ7. Expression modulation experiments determined that human PPTC7 dictates cellular CoQ content. Using two different approaches (PPTC7 over-expression and caloric restriction), we demonstrated that PPTC7 facilitates and improves the human cell adaptation to respiratory conditions. Moreover, we determined that the physiological role of PPTC7 takes place in the adaptation to starvation and pro-oxidant conditions, facilitating the induction of mitochondrial metabolism while preventing the accumulation of ROS. Here we unveil the first post-translational mechanism regulating CoQ biosynthesis in humans and propose targeting the induction of PPTC7 activity/expression for the treatment of CoQ-related mitochondrial diseases.
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http://dx.doi.org/10.1016/j.bbabio.2018.09.369DOI Listing
November 2018

Bioavailability of coenzyme Q10 supplements depends on carrier lipids and solubilization.

Nutrition 2019 01 27;57:133-140. Epub 2018 Jun 27.

Universidad Pablo de Olavide, Centro Andaluz de Biología del Desarrollo, CABD-CSIC, CIBERER, Instituto de Salud Carlos III, Sevilla, Spain.

Objectives: Bioavailability of supplements with coenzyme Q10 (CoQ) in humans seems to depend on the excipients of formulations and on physiological characteristics of the individuals. The aim of this study was to determine which factors presented in CoQ supplements affect the different response to CoQ in humans.

Methods: We tested seven different supplement formulations containing 100 mg of CoQ in 14 young, healthy individuals. Bioavailability was measured as area under the curve of plasma CoQ levels over 48 h after ingestion of a single dose. Measurements were repeated in the same group of 14 volunteers in a double-blind crossover design with a minimum of 4 wk washout between intakes.

Results: Bioavailability of the formulations showed large differences that were statistically significant. The two best absorbable formulations were soft-gel capsules containing ubiquinone (oxidized CoQ) or ubiquinol (reduced CoQ). The matrix used to dissolve CoQ and the proportion and addition of preservatives such as vitamin C affected the bioavailability of CoQ. Although control measurements documented that all formulations contained 100 mg of either CoQ or ubiquinol, some of the participants showed high and others lower capacity to reach high increase of CoQ in blood, indicating the participation of individual unknown physiological factors.

Conclusion: This study highlights the importance of individually adapted selection of best formulations to reach the highest bioavailability of CoQ in humans.
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http://dx.doi.org/10.1016/j.nut.2018.05.020DOI Listing
January 2019

Mitochondrial dysfunction in metabolism and ageing: shared mechanisms and outcomes?

Biogerontology 2018 12 24;19(6):461-480. Epub 2018 Aug 24.

Centro Andaluz de Biología del Desarrollo, CABD-CSIC, CIBERER, Instituto de Salud Carlos III, Universidad Pablo de Olavide, Carretera de Utrera km. 1, 41013, Seville, Spain.

Mitochondria are key in the metabolism of aerobic organisms and in ageing progression and age-related diseases. Mitochondria are essential for obtaining ATP from glucose and fatty acids but also in many other essential functions in cells including aminoacids metabolism, pyridine synthesis, phospholipid modifications and calcium regulation. On the other hand, the activity of mitochondria is also the principal source of reactive oxygen species in cells. Ageing and chronic age-related diseases are associated with the deregulation of cell metabolism and dysfunction of mitochondria. Cell metabolism is controlled by three major nutritional sensors: mTOR, AMPK and Sirtuins. These factors control mitochondrial biogenesis and dynamics by regulating fusion, fission and turnover through mito- and autophagy. A complex interaction between the activity of these nutritional sensors, mitochondrial biogenesis rate and dynamics exists and affect ageing, age-related diseases including metabolic disease. Further, mitochondria maintain a constant communication with nucleus modulating gene expression and modifying epigenetics. In this review we highlight the importance of mitochondria in ageing and the repercussion in the progression of age-related diseases and metabolic disease.
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http://dx.doi.org/10.1007/s10522-018-9768-2DOI Listing
December 2018

Editorial: Coenzyme Q Redox State and Cellular Homeostasis.

Front Physiol 2018 30;9:912. Epub 2018 Jul 30.

Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC, and CIBERER, ISCIII, Seville, Spain.

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http://dx.doi.org/10.3389/fphys.2018.00912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6077213PMC
July 2018

The Impact of Aging, Calorie Restriction and Dietary Fat on Autophagy Markers and Mitochondrial Ultrastructure and Dynamics in Mouse Skeletal Muscle.

J Gerontol A Biol Sci Med Sci 2019 05;74(6):760-769

Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Campus de Excelencia Internacional Agroalimentario, ceiA3, Spain.

Loss of skeletal muscle mass and function is a hallmark of aging. This phenomenon has been related to a dysregulation of mitochondrial function and proteostasis. Calorie restriction (CR) has been demonstrated to delay aging and preserve function until late in life, particularly in muscle. Recently, we reported the type of dietary fat plays an important role in determining life span extension with 40% CR in male mice. In these conditions, lard fed mice showed an increased longevity compared to mice fed soybean or fish oils. In this article, we analyze the effect of 40% CR on muscle mitochondrial mass, autophagy, and mitochondrial dynamics markers in mice fed these diets. In CR fed animals, lard preserved muscle fibers structure, mitochondrial ultrastructure, and fission/fusion dynamics and autophagy, not only compared to control animals, but also compared with CR mice fed soybean and fish oils as dietary fat. We focus our discussion on dietary fatty acid saturation degree as an essential predictor of life span extension in CR mice.
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http://dx.doi.org/10.1093/gerona/gly161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6521922PMC
May 2019

Physical Exercise During Pregnancy Prevents Cognitive Impairment Induced by Amyloid-β in Adult Offspring Rats.

Mol Neurobiol 2019 Mar 7;56(3):2022-2038. Epub 2018 Jul 7.

Programa de Pós-Graduação em Ciências Biológicas - Bioquímica, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil.

Alzheimer's disease (AD) is the main aging-associated neurodegenerative disorder and is characterized by mitochondrial dysfunction, oxidative stress, synaptic failure, and cognitive decline. It has been a challenge to find disease course-modifying treatments. However, several studies demonstrated that regular physical activity and exercise are capable of promoting brain health by improving the cognitive function. Maternal lifestyle, including regular exercise during pregnancy, has also been shown to influence fetal development and disease susceptibility in adulthood through fetal metabolism programming. Here, we investigated the potential neuroprotective role of regular maternal swimming, before and during pregnancy, against amyloid-β neurotoxicity in the adult offspring. Behavioral and neurochemical analyses were performed 14 days after male offspring received a single, bilateral, intracerebroventricular (icv) injection of amyloid-β oligomers (AβOs). AβOs-injected rats of the sedentary maternal group exhibited learning and memory deficits, along with reduced synaptophysin, brain-derived neurotrophic factor (BDNF) levels, and alterations of mitochondrial function. Strikingly, the offspring of the sedentary maternal group had AβOs-induced behavioral alterations that were prevented by maternal exercise. This effect was accompanied by preventing the alteration of synaptophysin levels in the offspring of exercised dams. Additionally, offspring of the maternal exercise group exhibited an augmentation of functional mitochondria, as indicated by increases in mitochondrial mass and membrane potential, α-ketoglutarate dehydrogenase, and cytochrome c oxidase enzymes activities. Moreover, maternal exercise during pregnancy induced long-lasting modulation of fusion and fission proteins, Mfn1 and Drp1, respectively. Overall, our data demonstrates a potential protective effect of exercise during pregnancy against AβOs-induced neurotoxicity in the adult offspring brain, by mitigating the neurodegenerative process triggered by Alzheimer-associated AβOs through programming the brain metabolism.
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http://dx.doi.org/10.1007/s12035-018-1210-xDOI Listing
March 2019

Essential Physiological Differences Characterize Short- and Long-Lived Strains of Drosophila melanogaster.

J Gerontol A Biol Sci Med Sci 2019 11;74(12):1835-1843

Institute for Cell and Molecular Biosciences, Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne, UK.

Aging is a multifactorial process which affects all animals. Aging as a result of damage accumulation is the most accepted explanation but the proximal causes remain to be elucidated. There is also evidence indicating that aging has an important genetic component. Animal species age at different rates and specific signaling pathways, such as insulin/insulin-like growth factor, can regulate life span of individuals within a species by reprogramming cells in response to environmental changes. Here, we use an unbiased approach to identify novel factors that regulate life span in Drosophila melanogaster. We compare the transcriptome and metabolome of two wild-type strains used widely in aging research: short-lived Dahomey and long-lived Oregon R flies. We found that Dahomey flies carry several traits associated with short-lived individuals and species such as increased lipoxidative stress, decreased mitochondrial gene expression, and increased Target of Rapamycin signaling. Dahomey flies also have upregulated octopamine signaling known to stimulate foraging behavior. Accordingly, we present evidence that increased foraging behavior, under laboratory conditions where nutrients are in excess increases damage generation and accelerates aging. In summary, we have identified several new pathways, which influence longevity highlighting the contribution and importance of the genetic component of aging.
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http://dx.doi.org/10.1093/gerona/gly143DOI Listing
November 2019

Molecular diagnosis of coenzyme Q deficiency: an update.

Expert Rev Mol Diagn 2018 06 30;18(6):491-498. Epub 2018 May 30.

a Department of Genetic and Clinical Biochemistry , Institut de Recerca Sant Joan de Déu, and CIBER de Enfermedades Raras (CIBERER) , Barcelona , Spain.

Introduction: Coenzyme Q (CoQ) deficiency syndromes comprise a growing number of genetic disorders. While primary CoQ deficiency syndromes are rare diseases, secondary deficiencies have been related to both genetic and environmental conditions, which are the main causes of biochemical CoQ deficiency. The diagnosis is the essential first step for planning future treatment strategies, as the potential treatability of CoQ deficiency is the most critical issue for the patients. Areas covered: While the quickest and most effective tool to define a CoQ-deficient status is its biochemical determination in biological fluids or tissues, this quantification does not provide a definite diagnosis of a CoQ-deficient status nor insight about the genetic etiology of the disease. The different laboratory tests to check for CoQ deficiency are evaluated in order to choose the best diagnostic pathway for the patient. Expert commentary: New insights are being discovered about the implication of new proteins in the intricate CoQ biosynthetic pathway. These insights reinforce the idea that next generation sequencing diagnostic strategies are the unique alternative in terms of rapid and accurate molecular diagnosis of CoQ deficiency.
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http://dx.doi.org/10.1080/14737159.2018.1478290DOI Listing
June 2018

Overexpression of CYB5R3 and NQO1, two NAD -producing enzymes, mimics aspects of caloric restriction.

Aging Cell 2018 08 28;17(4):e12767. Epub 2018 Apr 28.

Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.

Calorie restriction (CR) is one of the most robust means to improve health and survival in model organisms. CR imposes a metabolic program that leads to increased stress resistance and delayed onset of chronic diseases, including cancer. In rodents, CR induces the upregulation of two NADH-dehydrogenases, namely NAD(P)H:quinone oxidoreductase 1 (Nqo1) and cytochrome b reductase 3 (Cyb5r3), which provide electrons for energy metabolism. It has been proposed that this upregulation may be responsible for some of the beneficial effects of CR, and defects in their activity are linked to aging and several age-associated diseases. However, it is unclear whether changes in metabolic homeostasis solely through upregulation of these NADH-dehydrogenases have a positive impact on health and survival. We generated a mouse that overexpresses both metabolic enzymes leading to phenotypes that resemble aspects of CR including a modest increase in lifespan, greater physical performance, a decrease in chronic inflammation, and, importantly, protection against carcinogenesis, one of the main hallmarks of CR. Furthermore, these animals showed an enhancement of metabolic flexibility and a significant upregulation of the NAD /sirtuin pathway. The results highlight the importance of these NAD producers for the promotion of health and extended lifespan.
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http://dx.doi.org/10.1111/acel.12767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6052403PMC
August 2018
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