TY  - JOUR
AB  - The alternative oxidase, AOX, provides a by-pass of the cytochrome segment of the mitochondrial respiratory chain when the chain is unavailable. AOX is absent from mammals, but AOX from Ciona intestinalis is benign when expressed in mice. Although non-protonmotive, so does not contribute directly to ATP production, it has been shown to modify and in some cases rescue phenotypes of respiratory-chain disease models. Here we studied the effect of C. intestinalis AOX on mice engineered to express a disease-equivalent mutant of Uqcrh, encoding the hinge subunit of mitochondrial respiratory complex III, which results in a complex metabolic phenotype beginning at 4-5 weeks, rapidly progressing to lethality within a further 6-7 weeks. AOX expression delayed the onset of this phenotype by several weeks, but provided no long-term benefit. We discuss the significance of this finding in light of the known and hypothesized effects of AOX on metabolism, redox homeostasis, oxidative stress and cell signaling. Although not a panacea, the ability of AOX to mitigate disease onset and progression means it could be useful in treatment.
AU  - Jacobs, H.T.*
AU  - Szibor, M.*
AU  - Rathkolb, B.
AU  - da Silva Buttkus, P.
AU  - Aguilar-Pimentel, J.A.
AU  - Amarie, O.V.
AU  - Becker, L.
AU  - Calzada-Wack, J.
AU  - Dragano, N.R.V.
AU  - Garrett, L.
AU  - Gerlini, R.
AU  - Hölter, S.M.
AU  - Klein-Rodewald, T.
AU  - Kraiger, M.
AU  - Leuchtenberger, S.
AU  - Marschall, S.
AU  - Östereicher, M.A.
AU  - Pfannes, K.
AU  - Sanz-Moreno, A.
AU  - Seisenberger, C.
AU  - Spielmann, N.
AU  - Stoeger, C.
AU  - Wurst, W.
AU  - Fuchs, H.
AU  - Hrabě de Angelis, M.
AU  - Gailus-Durner, V.
C1  - 67894
C2  - 54372
CY  - Radarweg 29, 1043 Nx Amsterdam, Netherlands
TI  - AOX delays the onset of the lethal phenotype in a mouse model of Uqcrh (complex III) disease.
JO  - Biochim. Biophys. Acta-Mol. Basis Dis.
VL  - 1869
IS  - 7
PB  - Elsevier
PY  - 2023
SN  - 0925-4439
ER  - 

TY  - JOUR
AB  - SARS-CoV-2 remains an acute threat to human health, endangering hospital capacities worldwide. Previous studies have aimed at informing pathophysiologic understanding and identification of disease indicators for risk assessment, monitoring, and therapeutic guidance. While findings start to emerge in the general population, observations in high-risk patients with complex pre-existing conditions are limited. We addressed the gap of existing knowledge with regard to a differentiated understanding of disease dynamics in SARS-CoV-2 infection while specifically considering disease stage and severity. We biomedically characterized quantitative proteomics in a hospitalized cohort of COVID-19 patients with mild to severe symptoms suffering from different (co)-morbidities in comparison to both healthy individuals and patients with non-COVID related inflammation. Deep clinical phenotyping enabled the identification of individual disease trajectories in COVID-19 patients. By the use of the individualized disease phase assignment, proteome analysis revealed a severity dependent general type-2-centered host response side-by-side with a disease specific antiviral immune reaction in early disease. The identification of phenomena such as neutrophil extracellular trap (NET) formation and a pro-coagulatory response characterizing severe disease was successfully validated in a second cohort. Together with the regulation of proteins related to SARS-CoV-2-specific symptoms identified by proteome screening, we not only confirmed results from previous studies but provide novel information for biomarker and therapy development.
AU  - Bauer, A.
AU  - Pachl, E.
AU  - Hellmuth, J.C.*
AU  - Kneidinger, N.
AU  - Heydarian, M.*
AU  - Frankenberger, M.*
AU  - Stubbe, H.C.*
AU  - Ryffel, B.*
AU  - Petrera, A.
AU  - Hauck, S.M.
AU  - Behr, J.*
AU  - Kaiser, R.*
AU  - Scherer, C.*
AU  - Deng, L.
AU  - Teupser, D.*
AU  - Ahmidi, N.*
AU  - Muenchhoff, M.*
AU  - Schubert, B.
AU  - Hilgendorff, A.
C1  - 66615
C2  - 53248
CY  - Radarweg 29, 1043 Nx Amsterdam, Netherlands
TI  - Proteomics reveals antiviral host response and NETosis during acute COVID-19 in high-risk patients.
JO  - Biochim. Biophys. Acta-Mol. Basis Dis.
VL  - 1869
IS  - 2
PB  - Elsevier
PY  - 2022
SN  - 0925-4439
ER  - 

TY  - JOUR
AB  - Isolated methylmalonic aciduria (MMAuria) is primarily caused by deficiency of methylmalonyl-CoA mutase (MMUT or MUT). Biochemically, MUT deficiency results in the accumulation of methylmalonic acid (MMA), propionyl-camitine (C3) and other metabolites. Patients often exhibit lethargy, failure to thrive and metabolic decompensation leading to coma or even death, with kidney and neurological impairment frequently identified in the long-term. Here, we report a hemizygous mouse model which combines a knock-in (ki) missense allele of Mut with a knock-out (ko) allele (Mut-ko/ki mice) that was fed a 51%-protein diet from day 12 of life, constituting a bespoke model of MMAuria. Under this diet, mutant mice developed a pronounced metabolic phenotype characterized by drastically increased blood levels of MMA and C3 compared to their littermate controls (Mut-ki/wt). With this bespoke mouse model, we performed a standardized phenotypic screen to assess the whole-body impairments associated with this strong metabolic condition. We found that Mut-ko/ki mice show common clinical manifestations of MMAuria, including pronounced failure to thrive, indications of mild neurological and kidney dysfunction, and degenerative morphological changes in the liver, along with less well described symptoms such as cardiovascular and hematological abnormalities. The analyses also reveal so far unknown disease characteristics, including low bone mineral density, anxiety-related behaviour and ovarian atrophy. This first phenotypic screening of a MMAuria mouse model confirms its relevance to human disease, reveals new alterations associated with MUT deficiency, and suggests a series of quantifiable readouts that can be used to evaluate potential treatment strategies.
AU  - Lucienne, M.*
AU  - Aguilar-Pimentel, J.A.
AU  - Amarie, O.V.
AU  - Becker, L.
AU  - Calzada-Wack, J.
AU  - Da Silva-Buttkus, P.
AU  - Garrett, L.
AU  - Hölter, S.M.
AU  - Mayer-Kuckuk, P.
AU  - Rathkolb, B.
AU  - Rozman, J.
AU  - Spielmann, N.
AU  - Treise, I.
AU  - Busch, D.H.*
AU  - Klopstock, T.*
AU  - Schmidt-Weber, C.B.
AU  - Wolf, E.*
AU  - Wurst, W.
AU  - Forny, M.*
AU  - Mathis, D.*
AU  - Fingerhut, R.*
AU  - Froese, D.S.*
AU  - Gailus-Durner, V.
AU  - Fuchs, H.
AU  - Hrabě de Angelis, M.
AU  - Baumgartner, M.R.*
C1  - 57428
C2  - 47769
CY  - Radarweg 29, 1043 Nx Amsterdam, Netherlands
TI  - In-depth phenotyping reveals common and novel disease symptoms in a hemizygous knock-in mouse model (Mut-ko/ki) of mut-type methylmalonic aciduria.
JO  - Biochim. Biophys. Acta-Mol. Basis Dis.
VL  - 1866
IS  - 3
PB  - Elsevier
PY  - 2020
SN  - 0925-4439
ER  - 

TY  - JOUR
AB  - Objectives: Investigation of the effect of SGLT2 inhibition by empagliflozin on left ventricular function in a model of diabetic cardiomyopathy.Background: SGLT2 inhibition is a new strategy to treat diabetes. In the EMPA-REG Outcome trial empagliflozin treatment reduced cardiovascular and overall mortality in patients with diabetes presumably due to beneficial cardiac effects, leading to reduced heart failure hospitalization. The relevant mechanisms remain currently elusive but might be mediated by a shift in cardiac substrate utilization leading to improved energetic supply to the heart.Methods: We used db/db mice on high-fat western diet with or without empagliflozin treatment as a model of severe diabetes. Left ventricular function was assessed by pressure catheter with or without dobutamine stress.Results: Treatment with empagliflozin significantly increased glycosuria, improved glucose metabolism, ameliorated left ventricular diastolic function and reduced mortality of mice. This was associated with reduced cardiac glucose concentrations and decreased calcium/calmodulin-dependent protein kinase (CaMKII) activation with subsequent less phosphorylation of the ryanodine receptor (RyR). No change of cardiac ketone bodies or branched-chain amino acid (BCAA) metabolites in serum was detected nor was cardiac expression of relevant catabolic enzymes for these substrates affected.Conclusions: In a murine model of severe diabetes empagliflozin-dependent SGLT2 inhibition improved diastolic function and reduced mortality. Improvement of diastolic function was likely mediated by reduced spontaneous diastolic sarcoplasmic reticulum (SR) calcium release but independent of changes in cardiac ketone and BCAA metabolism.
AU  - Moellmann, J.*
AU  - Klinkhammer, B.M.*
AU  - Droste, P.*
AU  - Kappel, B.*
AU  - Haj-Yehia, E.*
AU  - Maxeiner, S.*
AU  - Artati, A.
AU  - Adamski, J.
AU  - Boor, P.*
AU  - Schütt, K.*
AU  - Lopaschuk, G.D.*
AU  - Verma, S.*
AU  - Marx, N.*
AU  - Lehrke, M.*
C1  - 59138
C2  - 48701
CY  - Radarweg 29, 1043 Nx Amsterdam, Netherlands
TI  - Empagliflozin improves left ventricular diastolic function of db/db mice.
JO  - Biochim. Biophys. Acta-Mol. Basis Dis.
VL  - 1866
IS  - 8
PB  - Elsevier
PY  - 2020
SN  - 0925-4439
ER  - 

TY  - JOUR
AB  - Mutations in the X chromosomal tRNA 2'-O-methyltransferase FTSJ1 cause intellectual disability (ID). Although the gene is ubiquitously expressed affected individuals present no consistent clinical features beyond ID. In order to study the pathological mechanism involved in the aetiology of FTSJ1 deficiency-related cognitive impairment, we generated and characterized an Ftsj1 deficient mouse line based on the gene trapped stem cell line RRD143. Apart from an impaired learning capacity these mice presented with several statistically significantly altered features related to behaviour, pain sensing, bone and energy metabolism, the immune and the hormone system as well as gene expression. These findings show that Ftsj1 deficiency in mammals is not phenotypically restricted to the brain but affects various organ systems. Re-examination of ID patients with FTSJ1 mutations from two previously reported families showed that several features observed in the mouse model were recapitulated in some of the patients. Though the clinical spectrum related to Ftsj1 deficiency in mouse and man is variable, we suggest that an increased pain threshold may be more common in patients with FTSJ1 deficiency. Our findings demonstrate novel roles for Ftsj1 in maintaining proper cellular and tissue functions in a mammalian organism.
AU  - Jensen, L.R.*
AU  - Garrett, L.
AU  - Hölter, S.M.
AU  - Rathkolb, B.
AU  - Rácz, I.
AU  - Adler, T.
AU  - Prehn, C.
AU  - Hans, W.
AU  - Rozman, J.
AU  - Becker, L.
AU  - Aguilar-Pimentel, J.A.
AU  - Puk, O.
AU  - Moreth, K.
AU  - Dopatka, M.*
AU  - Walther, D.J.*
AU  - von Bohlen Und Halbach, V.*
AU  - Rath, M.*
AU  - Delatycki, M.*
AU  - Bert, B.*
AU  - Fink, H.*
AU  - Blümlein, K.*
AU  - Ralser, M.*
AU  - Van Dijck, A.*
AU  - Kooy, F.*
AU  - Stark, Z.*
AU  - Müller, S.*
AU  - Scherthan, H.*
AU  - Gecz, J.*
AU  - Wurst, W.
AU  - Wolf, E.*
AU  - Zimmer, A.*
AU  - Klingenspor, M.*
AU  - Graw, J.
AU  - Klopstock, T.*
AU  - Busch, D.*
AU  - Adamski, J.
AU  - Fuchs, H.
AU  - Gailus-Durner, V.
AU  - Hrabě de Angelis, M.
AU  - von Bohlen und Halbach, O.*
AU  - Ropers, H.H.*
AU  - Kuss, A.W.*
C1  - 54985
C2  - 45962
CY  - Radarweg 29, 1043 Nx Amsterdam, Netherlands
SP  - 2083-2093
TI  - A mouse model for intellectual disability caused by mutations in the X-linked 2 '-O-methyltransferase Ftsj1 gene.
JO  - Biochim. Biophys. Acta-Mol. Basis Dis.
VL  - 1865
IS  - 9
PB  - Elsevier
PY  - 2018
SN  - 0925-4439
ER  - 

TY  - JOUR
AB  - Peri-conceptional exposure to maternal obesogenic nutrition is associated with in utero programming of later-life overweight and metabolic disease in the offspring. We aimed to investigate whether dietary intervention with a modified fatty acid quality in an obesogenic high-calorie (HC) diet during the preconception and gestational phases can improve unfavourable effects of an adipogenic maternal environment. In NMRI mice, peri-conceptional and gestational obesity was induced by feeding a HC diet (controls), and they were compared with dams on a fat-modified (Fat-mod) HC diet of the same energy content but enriched with medium-chain fatty acids (MCFAs) and adjusted to a decreased ratio of n-6 to n-3 long-chain polyunsaturated fatty acids (LC-PUFAs). Effects on maternal and placental outcomes at delivery (day 17.5 post coitum) were investigated. Despite comparable energy assimilation between the two groups of dams, the modified fatty acid composition of the high-caloric diet induced lower maternal body weight, weights of fat depots, adipocyte size, and hepatic fat accumulation compared to the unmodified HC diet group. Further, there was a trend towards lower fasting glucose, insulin and leptin concentrations in dams fed the Fat-mod HC diet. Phenotypic changes were accompanied by inhibition of transcript and protein expression of genes involved in hepatic de novo lipogenesis comprising PPARG2 and its target genes Fasn, Acaca, Fabp4, whereas regulation of other lipogenic factors (Srebf1, Nr1h3, Abca1) appeared to be more complex. The modified diet led to a sex-specific placental response by upregulating PPARG-dependent fatty acid transport gene expression in female versus male placentae. Qualitative modification of the fatty acid spectrum of a high-energy maternal diet, using a combination of both MCFAs and n-3 LC-PUFAs, seems to be a promising interventional approach to ameliorate the adipogenic milieu of mice before and during gestation.
AU  - Gimpfl, M.*
AU  - Rozman, J.
AU  - Dahlhoff, M.*
AU  - Kübeck, R.*
AU  - Blutke, A.*
AU  - Rathkolb, B.
AU  - Klingenspor, M.*
AU  - Hrabě de Angelis, M.
AU  - Öner-Sieben, S.*
AU  - Seibt, A.*
AU  - Roscher, A.A.*
AU  - Wolf, E.*
AU  - Ensenauer, R.*
C1  - 50560
C2  - 42379
CY  - Amsterdam
SP  - 1605-1614
TI  - Modification of the fatty acid composition of an obesogenic diet improves the maternal and placental metabolic environment in obese pregnant mice.
JO  - Biochim. Biophys. Acta-Mol. Basis Dis.
VL  - 1863
IS  - 6
PB  - Elsevier Science Bv
PY  - 2017
SN  - 0925-4439
ER  - 

TY  - JOUR
AB  - Vulnerability of the fetus upon maternal obesity can potentially occur during all developmental phases. We aimed at elaborating longer-term health outcomes of fetal overnutrition during the earliest stages of development. We utilized NMRI mice to induce pre-conceptional and gestational obesity and followed offspring outcomes in the absence of any postnatal obesogenic influences. Male adult offspring developed overweight, insulin resistance, hyperleptinemia, hyperuricemia and hepatic steatosis; all these features not being observed in females. Instead, those showed impaired fasting glucose and a reduced fat mass and adipocyte size. Influences of the interaction of maternal diet*sex concerned offspring genes involved in fatty liver disease, lipid droplet size regulation and fat mass expansion. These data suggest that a peri-conceptional obesogenic exposure is sufficient to shape offspring gene expression patterns and health outcomes in a sex- and organ-specific manner, indicating varying developmental vulnerabilities between sexes towards metabolic disease in response to maternal overnutrition.
AU  - Dahlhoff, M.*
AU  - Pfister, S.*
AU  - Blutke, A.*
AU  - Rozman, J.
AU  - Klingenspor, M.*
AU  - Deutsch, M.J.*
AU  - Rathkolb, B.
AU  - Fink, B.*
AU  - Gimpfl, M.*
AU  - Hrabě de Angelis, M.
AU  - Roscher, A.A.*
AU  - Wolf, E.*
AU  - Ensenauer, R.*
C1  - 28546
C2  - 33438
CY  - Amsterdam
SP  - 304–317
TI  - Peri-conceptional obesogenic exposure induces sex-specific programming of disease susceptibilities in adult mouse offspring.
JO  - Biochim. Biophys. Acta-Mol. Basis Dis.
VL  - 1842
IS  - 2
PB  - Elsevier Science
PY  - 2014
SN  - 0925-4439
ER  - 

TY  - JOUR
AB  - Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene represent the most common genetic cause of Parkinson's disease (PD). However, LRRK2 function and molecular mechanisms causing the parkinsonian phenotype remain widely unknown. Most of LRRK2 knockdown and overexpression models strengthen the relevance of LRRK2 in regulating neurite outgrowth. We have recently identified ARHGEF7 as the first guanine nucleotide exchange factor (GEF) of LRRK2. This GEF is influencing neurite outgrowth through regulation of actin polymerization. Here, we examined the expression profile of neuroblastoma cells with reduced LRRK2 and ARHGEF7 levels to identify additional partners of LRRK2 in this process. Tropomyosins (TPMs), and in particular TPM4, were the most interesting candidates next to other actin cytoskeleton regulating transcripts in this dataset. Subsequently, enhanced neurite branching was shown using primary hippocampal neurons of LRRK2 knockdown animals. Furthermore, we observed an enhanced number of growth cones per neuron and a mislocalization and dysregulation of ARHGEF7 and TPM4 in these neuronal compartments. Our results reveal a fascinating connection between the neurite outgrowth phenotype of LRRK2 models and the regulation of actin polymerization directing further investigations of LRRK2-related pathogenesis.
AU  - Häbig, K.*
AU  - Gellhaar, S.*
AU  - Heim, B.*
AU  - Djuric, V.*
AU  - Giesert, F.
AU  - Wurst, W.
AU  - Walter, C.*
AU  - Hentrich, T.*
AU  - Riess, O.*
AU  - Bonin, M.*
C1  - 28095
C2  - 32929
SP  - 2352-2367
TI  - LRRK2 guides the actin cytoskeleton at growth cones together with ARHGEF7 and Tropomyosin 4.
JO  - Biochim. Biophys. Acta-Mol. Basis Dis.
VL  - 1832
IS  - 12
PB  - Elsevier Science
PY  - 2013
SN  - 0925-4439
ER  - 

TY  - JOUR
AU  - Netzer, C.*
AU  - Bohlander, S.K.
AU  - Hinzke, M.*
AU  - Chen, Y.
AU  - Kohlhase, J.*
C1  - 3013
C2  - 23985
SP  - 386-391
TI  - Defining the heterochromatin localization and repression domains of SALL1.
JO  - Biochim. Biophys. Acta-Mol. Basis Dis.
VL  - 1762
PB  - Elsevier
PY  - 2006
SN  - 0925-4439
ER  - 

TY  - JOUR
AB  - The effect of exogenous phosphatidylcholine on structure and function of plasma membranes from HIV-1-producing cells and from their non-infected counterparts was determined. The membrane protein composition was not affected by phospholipid treatment. Membrane fluidity and Ca 2+-permeability were increased in virus-producing cells and in control cells after lipid treatment. The triacylglycerol content of the plasma membranes was increased in virus-producing cells after lipid treatment, whereas the content of phospholipid and cholesterol was not changed. The increased triacylglycerol content was in accordance with a relatively higher rate of [ 14C]oleic acid incorporation into triacylglycerols of the virus-producing cells after lipid treatment as shown by metabolic labeling. The results suggest that a latent cytopathic effect of HIV-infection becomes manifest if the cells are exposed to exogenous phospholipid and this may open a way to preferentially eliminate HIV-producing cells.
AU  - Kerler, F.
AU  - Hübner, C.
AU  - Erfle, V.
AU  - Buff, K.
C1  - 40498
C2  - 38536
SP  - 57-64
TI  - Exposure of HIV-infected cells to phospholipid leads to membrane alterations and selective growth retardation.
JO  - Biochim. Biophys. Acta-Mol. Basis Dis.
VL  - 1139
IS  - 1-2
PY  - 1992
SN  - 0925-4439
ER  -