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Article ; Online: Tricky Isomers—The Evolution of Analytical Strategies to Characterize Plasmalogens and Plasmanyl Ether Lipids

Jakob Koch / Katrin Watschinger / Ernst R. Werner / Markus A. Keller

Frontiers in Cell and Developmental Biology, Vol

2022 Volume 10

Abstract: Typically, glycerophospholipids are represented with two esterified fatty acids. However, by up to 20%, a significant proportion of this lipid class carries an ether-linked fatty alcohol side chain at the sn-1 position, generally referred to as ether ... ...

Abstract	Typically, glycerophospholipids are represented with two esterified fatty acids. However, by up to 20%, a significant proportion of this lipid class carries an ether-linked fatty alcohol side chain at the sn-1 position, generally referred to as ether lipids, which shape their specific physicochemical properties. Among those, plasmalogens represent a distinct subgroup characterized by an sn-1 vinyl-ether double bond. The total loss of ether lipids in severe peroxisomal defects such as rhizomelic chondrodysplasia punctata indicates their crucial contribution to diverse cellular functions. An aberrant ether lipid metabolism has also been reported in multifactorial conditions including Alzheimer’s disease. Understanding the underlying pathological implications is hampered by the still unclear exact functional spectrum of ether lipids, especially in regard to the differentiation between the individual contributions of plasmalogens (plasmenyl lipids) and their non-vinyl-ether lipid (plasmanyl) counterparts. A primary reason for this is that exact identification and quantification of plasmalogens and other ether lipids poses a challenging and usually labor-intensive task. Diverse analytical methods for the detection of plasmalogens have been developed. Liquid chromatography–tandem mass spectrometry is increasingly used to resolve complex lipid mixtures, and with optimized parameters and specialized fragmentation strategies, discrimination between ethers and plasmalogens is feasible. In this review, we recapitulate historic and current methodologies for the recognition and quantification of these important lipids and will discuss developments in this field that can contribute to the characterization of plasmalogens in high structural detail.
Keywords	ether lipid biosynthesis ; mass spectrometry ; phospholipid analytics ; PEDS1 ; plasmalogen physiology ; plasmenyl and plasmanyl isomers ; Biology (General) ; QH301-705.5
Subject code	572
Language	English
Publishing date	2022-04-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The Emerging Physiological Role of AGMO 10 Years after Its Gene Identification

Sabrina Sailer / Markus A. Keller / Ernst R. Werner / Katrin Watschinger

Life, Vol 11, Iss 2, p

2021 Volume 88

Abstract: The gene encoding alkylglycerol monooxygenase (AGMO) was assigned 10 years ago. So far, AGMO is the only known enzyme capable of catalysing the breakdown of alkylglycerols and lyso-alkylglycerophospholipids. With the knowledge of the genetic information, ...

Abstract	The gene encoding alkylglycerol monooxygenase (AGMO) was assigned 10 years ago. So far, AGMO is the only known enzyme capable of catalysing the breakdown of alkylglycerols and lyso-alkylglycerophospholipids. With the knowledge of the genetic information, it was possible to relate a potential contribution for mutations in the AGMO locus to human diseases by genome-wide association studies. A possible role for AGMO was implicated by genetic analyses in a variety of human pathologies such as type 2 diabetes, neurodevelopmental disorders, cancer, and immune defence. Deficient catabolism of stored lipids carrying an alkyl bond by an absence of AGMO was shown to impact on the overall lipid composition also outside the ether lipid pool. This review focuses on the current evidence of AGMO in human diseases and summarises experimental evidence for its role in immunity, energy homeostasis, and development in humans and several model organisms. With the progress in lipidomics platform and genetic identification of enzymes involved in ether lipid metabolism such as AGMO, it is now possible to study the consequence of gene ablation on the global lipid pool and further on certain signalling cascades in a variety of model organisms in more detail.
Keywords	AGMO ; tetrahydrobiopterin ; alkylglycerols ; plasmalogens ; neurodevelopment ; autism ; Science ; Q
Subject code	572
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The Impact of Non-Enzymatic Reactions and Enzyme Promiscuity on Cellular Metabolism during (Oxidative) Stress Conditions

Gabriel Piedrafita / Markus A Keller / Markus Ralser

Biomolecules, Vol 5, Iss 3, Pp 2101-

2015 Volume 2122

Abstract: Cellular metabolism assembles in a structurally highly conserved, but functionally dynamic system, known as the metabolic network. This network involves highly active, enzyme-catalyzed metabolic pathways that provide the building blocks for cell growth. ... ...

Abstract	Cellular metabolism assembles in a structurally highly conserved, but functionally dynamic system, known as the metabolic network. This network involves highly active, enzyme-catalyzed metabolic pathways that provide the building blocks for cell growth. In parallel, however, chemical reactivity of metabolites and unspecific enzyme function give rise to a number of side products that are not part of canonical metabolic pathways. It is increasingly acknowledged that these molecules are important for the evolution of metabolism, affect metabolic efficiency, and that they play a potential role in human disease—age-related disorders and cancer in particular. In this review we discuss the impact of oxidative and other cellular stressors on the formation of metabolic side products, which originate as a consequence of: (i) chemical reactivity or modification of regular metabolites; (ii) through modifications in substrate specificity of damaged enzymes; and (iii) through altered metabolic flux that protects cells in stress conditions. In particular, oxidative and heat stress conditions are causative of metabolite and enzymatic damage and thus promote the non-canonical metabolic activity of the cells through an increased repertoire of side products. On the basis of selected examples, we discuss the consequences of non-canonical metabolic reactivity on evolution, function and repair of the metabolic network.
Keywords	oxidative stress ; reactive oxygen species ; metabolic damage ; metabolite repair ; enzyme promiscuity ; underground metabolism ; Biology (General) ; QH301-705.5 ; Science ; Q
Subject code	570
Language	English
Publishing date	2015-09-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Phospholipid Acyl Chain Diversity Controls the Tissue-Specific Assembly of Mitochondrial Cardiolipins

Gregor Oemer / Jakob Koch / Yvonne Wohlfarter / Mohammad T. Alam / Katharina Lackner / Sabrina Sailer / Lukas Neumann / Herbert H. Lindner / Katrin Watschinger / Markus Haltmeier / Ernst R. Werner / Johannes Zschocke / Markus A. Keller

Cell Reports, Vol 30, Iss 12, Pp 4281-4291.e

2020 Volume 4

Abstract: Summary: Cardiolipin (CL) is a phospholipid specific for mitochondrial membranes and crucial for many core tasks of this organelle. Its acyl chain configurations are tissue specific, functionally important, and generated via post-biosynthetic remodeling. ...

Abstract	Summary: Cardiolipin (CL) is a phospholipid specific for mitochondrial membranes and crucial for many core tasks of this organelle. Its acyl chain configurations are tissue specific, functionally important, and generated via post-biosynthetic remodeling. However, this process lacks the necessary specificity to explain CL diversity, which is especially evident for highly specific CL compositions in mammalian tissues. To investigate the so far elusive regulatory origin of CL homeostasis in mice, we combine lipidomics, integrative transcriptomics, and data-driven machine learning. We demonstrate that not transcriptional regulation, but cellular phospholipid compositions are closely linked to the tissue specificity of CL patterns allowing artificial neural networks to precisely predict cross-tissue CL compositions in a consistent mechanistic specificity rationale. This is especially relevant for the interpretation of disease-related perturbations of CL homeostasis, by allowing differentiation between specific aberrations in CL metabolism and changes caused by global alterations in cellular (phospho-)lipid metabolism. : The lipid architecture of biomembranes is crucial for their cellular functions. The regulatory origins of the strong tissue specificity of cardiolipins, a vital mitochondrial phospholipid class, were so far largely unresolved. Oemer et al. find that a single mechanism explains cardiolipin diversity across tissues on basis of the phospholipid environment. Keywords: cardiolipin, phospholipids, structural diversity, mouse tissue-specificity, membrane lipids, mitochondria, LC-MS/MS, lipidomics, machine learning, artificial neural network
Keywords	Biology (General) ; QH301-705.5
Language	English
Publishing date	2020-03-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: CHD1 controls H3.3 incorporation in adult brain chromatin to maintain metabolic homeostasis and normal lifespan

Ines Schoberleitner / Ingo Bauer / Anming Huang / Evgeniya N. Andreyeva / Johanna Sebald / Katharina Pascher / Dietmar Rieder / Melanie Brunner / Valerie Podhraski / Gregor Oemer / Daniel Cázarez-García / Leila Rieder / Markus A. Keller / Robert Winkler / Dmitry V. Fyodorov / Alexandra Lusser

Cell Reports, Vol 37, Iss 1, Pp 109769- (2021)

2021

Abstract: Summary: The ATP-dependent chromatin remodeling factor CHD1 is essential for the assembly of variant histone H3.3 into paternal chromatin during sperm chromatin remodeling in fertilized eggs. It remains unclear, however, if CHD1 has a similar role in ... ...

Abstract	Summary: The ATP-dependent chromatin remodeling factor CHD1 is essential for the assembly of variant histone H3.3 into paternal chromatin during sperm chromatin remodeling in fertilized eggs. It remains unclear, however, if CHD1 has a similar role in normal diploid cells. Using a specifically tailored quantitative mass spectrometry approach, we show that Chd1 disruption results in reduced H3.3 levels in heads of Chd1 mutant flies. Chd1 deletion perturbs brain chromatin structure in a similar way as H3.3 deletion and leads to global de-repression of transcription. The physiological consequences are reduced food intake, metabolic alterations, and shortened lifespan. Notably, brain-specific CHD1 expression rescues these phenotypes. We further demonstrate a strong genetic interaction between Chd1 and H3.3 chaperone Hira. Thus, our findings establish CHD1 as a factor required for the assembly of H3.3-containing chromatin in adult cells and suggest a crucial role for CHD1 in the brain as a regulator of organismal health and longevity.
Keywords	epigenetics ; histone chaperone ; heterochromatin ; aging ; longevity ; metabolic disease ; Biology (General) ; QH301-705.5
Subject code	572
Language	English
Publishing date	2021-10-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The self-inhibitory nature of metabolic networks and its alleviation through compartmentalization

Mohammad Tauqeer Alam / Viridiana Olin-Sandoval / Anna Stincone / Markus A. Keller / Aleksej Zelezniak / Ben F. Luisi / Markus Ralser

Nature Communications, Vol 8, Iss 1, Pp 1-

2017 Volume 13

Abstract: Metabolites act as enzyme inhibitors, but their global impact on metabolism has scarcely been considered. Here, the authors generate a human genome-wide metabolite-enzyme inhibition network, and find that inhibition occurs largely due to limited ... ...

Abstract	Metabolites act as enzyme inhibitors, but their global impact on metabolism has scarcely been considered. Here, the authors generate a human genome-wide metabolite-enzyme inhibition network, and find that inhibition occurs largely due to limited structural diversity of metabolites, leading to a global constraint on metabolism which subcellular compartmentalization minimizes.
Keywords	Science ; Q
Language	English
Publishing date	2017-07-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Inhibition of triosephosphate isomerase by phosphoenolpyruvate in the feedback-regulation of glycolysis

Nana-Maria Grüning / Dijun Du / Markus A. Keller / Ben F. Luisi / Markus Ralser

Open Biology, Vol 4, Iss

2014 Volume 3

Abstract: The inhibition of triosephosphate isomerase (TPI) in glycolysis by the pyruvate kinase (PK) substrate phosphoenolpyruvate (PEP) results in a newly discovered feedback loop that counters oxidative stress in cancer and actively respiring cells. The ... ...

Abstract	The inhibition of triosephosphate isomerase (TPI) in glycolysis by the pyruvate kinase (PK) substrate phosphoenolpyruvate (PEP) results in a newly discovered feedback loop that counters oxidative stress in cancer and actively respiring cells. The mechanism underlying this inhibition is illuminated by the co-crystal structure of TPI with bound PEP at 1.6 Å resolution, and by mutational studies guided by the crystallographic results. PEP is bound to the catalytic pocket of TPI and occludes substrate, which accounts for the observation that PEP competitively inhibits the interconversion of glyceraldehyde-3-phosphate and dihydroxyacetone phosphate. Replacing an isoleucine residue located in the catalytic pocket of TPI with valine or threonine altered binding of substrates and PEP, reducing TPI activity in vitro and in vivo. Confirming a TPI-mediated activation of the pentose phosphate pathway (PPP), transgenic yeast cells expressing these TPI mutations accumulate greater levels of PPP intermediates and have altered stress resistance, mimicking the activation of the PK–TPI feedback loop. These results support a model in which glycolytic regulation requires direct catalytic inhibition of TPI by the pyruvate kinase substrate PEP, mediating a protective metabolic self-reconfiguration of central metabolism under conditions of oxidative stress.
Keywords	glycolysis ; triosephosphate isomerase ; phosphoenolpyruvate ; pyruvate kinase ; feedback loop ; Biology (General) ; QH301-705.5
Subject code	570 ; 500
Language	English
Publishing date	2014-01-01T00:00:00Z
Publisher	The Royal Society
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: When the genome bluffs

Sabrina Sailer / Stefan Coassin / Katharina Lackner / Caroline Fischer / Eileen McNeill / Gertraud Streiter / Christian Kremser / Manuel Maglione / Catherine M. Green / Daniela Moralli / Alexander R. Moschen / Markus A. Keller / Georg Golderer / Gabriele Werner-Felmayer / Irmgard Tegeder / Keith M. Channon / Benjamin Davies / Ernst R. Werner / Katrin Watschinger

Cell & Bioscience, Vol 11, Iss 1, Pp 1-

a tandem duplication event during generation of a novel Agmo knockout mouse model fools routine genotyping

2021 Volume 10

Abstract: Abstract Background Genome editing in mice using either classical approaches like homologous recombination or CRISPR/Cas9 has been reported to harbor off target effects (insertion/deletion, frame shifts or gene segment duplications) that lead to ... ...

Abstract	Abstract Background Genome editing in mice using either classical approaches like homologous recombination or CRISPR/Cas9 has been reported to harbor off target effects (insertion/deletion, frame shifts or gene segment duplications) that lead to mutations not only in close proximity to the target site but also outside. Only the genomes of few engineered mouse strains have been sequenced. Since the role of the ether-lipid cleaving enzyme alkylglycerol monooxygenase (AGMO) in physiology and pathophysiology remains enigmatic, we created a knockout mouse model for AGMO using EUCOMM stem cells but unforeseen genotyping issues that did not agree with Mendelian distribution and enzyme activity data prompted an in-depth genomic validation of the mouse model. Results We report a gene segment tandem duplication event that occurred during the generation of an Agmo knockout-first allele by homologous recombination. Only low homology was seen between the breakpoints. While a single copy of the recombinant 18 kb cassette was integrated correctly around exon 2 of the Agmo gene, whole genome nanopore sequencing revealed a 94 kb duplication in the Agmo locus that contains Agmo wild-type exons 1–3. The duplication fooled genotyping by routine PCR, but could be resolved using qPCR-based genotyping, targeted locus amplification sequencing and nanopore sequencing. Despite this event, this Agmo knockout mouse model lacks AGMO enzyme activity and can therefore be used to study its physiological role. Conclusions A duplication event occurred at the exact locus of the homologous recombination and was not detected by conventional quality control filters such as FISH or long-range PCR over the recombination sites. Nanopore sequencing provides a cost convenient method to detect such underrated off-target effects, suggesting its use for additional quality assessment of gene editing in mice and also other model organisms.
Keywords	Homologous recombination ; Mouse models ; Ether lipid metabolism ; Genomic structural variation ; Alkylglycerol monooxygenase ; Biotechnology ; TP248.13-248.65 ; Biology (General) ; QH301-705.5 ; Biochemistry ; QD415-436
Subject code	572
Language	English
Publishing date	2021-03-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Remission of obesity and insulin resistance is not sufficient to restore mitochondrial homeostasis in visceral adipose tissue

Alba Gonzalez-Franquesa / Pau Gama-Perez / Marta Kulis / Karolina Szczepanowska / Norma Dahdah / Sonia Moreno-Gomez / Ana Latorre-Pellicer / Rebeca Fernández-Ruiz / Antoni Aguilar-Mogas / Anne Hoffman / Erika Monelli / Sara Samino / Joan Miró-Blanch / Gregor Oemer / Xavier Duran / Estrella Sanchez-Rebordelo / Marc Schneeberger / Merce Obach / Joel Montane /

Giancarlo Castellano / Vicente Chapaprieta / Wenfei Sun / Lourdes Navarro / Ignacio Prieto / Carlos Castaño / Anna Novials / Ramon Gomis / Maria Monsalve / Marc Claret / Mariona Graupera / Guadalupe Soria / Christian Wolfrum / Joan Vendrell / Sonia Fernández-Veledo / Jose Antonio Enríquez / Angel Carracedo / José Carlos Perales / Rubén Nogueiras / Laura Herrero / Aleksandra Trifunovic / Markus A. Keller / Oscar Yanes / Marta Sales-Pardo / Roger Guimerà / Matthias Blüher / José Ignacio Martín-Subero / Pablo M. Garcia-Roves

Redox Biology, Vol 54, Iss , Pp 102353- (2022)

2022

Abstract: Metabolic plasticity is the ability of a biological system to adapt its metabolic phenotype to different environmental stressors. We used a whole-body and tissue-specific phenotypic, functional, proteomic, metabolomic and transcriptomic approach to ... ...

Abstract	Metabolic plasticity is the ability of a biological system to adapt its metabolic phenotype to different environmental stressors. We used a whole-body and tissue-specific phenotypic, functional, proteomic, metabolomic and transcriptomic approach to systematically assess metabolic plasticity in diet-induced obese mice after a combined nutritional and exercise intervention. Although most obesity and overnutrition-related pathological features were successfully reverted, we observed a high degree of metabolic dysfunction in visceral white adipose tissue, characterized by abnormal mitochondrial morphology and functionality. Despite two sequential therapeutic interventions and an apparent global healthy phenotype, obesity triggered a cascade of events in visceral adipose tissue progressing from mitochondrial metabolic and proteostatic alterations to widespread cellular stress, which compromises its biosynthetic and recycling capacity. In humans, weight loss after bariatric surgery showed a transcriptional signature in visceral adipose tissue similar to our mouse model of obesity reversion. Overall, our data indicate that obesity prompts a lasting metabolic fingerprint that leads to a progressive breakdown of metabolic plasticity in visceral adipose tissue.
Keywords	Obesity ; Metabolic plasticity ; Visceral adipose tissue ; Mitochondrial dysfunction ; Exercise ; Caloric restriction ; Medicine (General) ; R5-920 ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2022-08-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Self-establishing communities enable cooperative metabolite exchange in a eukaryote

Kate Campbell / Jakob Vowinckel / Michael Mülleder / Silke Malmsheimer / Nicola Lawrence / Enrica Calvani / Leonor Miller-Fleming / Mohammad T Alam / Stefan Christen / Markus A Keller / Markus Ralser

eLife, Vol

2015 Volume 4

Abstract: Metabolite exchange among co-growing cells is frequent by nature, however, is not necessarily occurring at growth-relevant quantities indicative of non-cell-autonomous metabolic function. Complementary auxotrophs of Saccharomyces cerevisiae amino acid ... ...

Abstract	Metabolite exchange among co-growing cells is frequent by nature, however, is not necessarily occurring at growth-relevant quantities indicative of non-cell-autonomous metabolic function. Complementary auxotrophs of Saccharomyces cerevisiae amino acid and nucleotide metabolism regularly fail to compensate for each other's deficiencies upon co-culturing, a situation which implied the absence of growth-relevant metabolite exchange interactions. Contrastingly, we find that yeast colonies maintain a rich exometabolome and that cells prefer the uptake of extracellular metabolites over self-synthesis, indicators of ongoing metabolite exchange. We conceived a system that circumvents co-culturing and begins with a self-supporting cell that grows autonomously into a heterogeneous community, only able to survive by exchanging histidine, leucine, uracil, and methionine. Compensating for the progressive loss of prototrophy, self-establishing communities successfully obtained an auxotrophic composition in a nutrition-dependent manner, maintaining a wild-type like exometabolome, growth parameters, and cell viability. Yeast, as a eukaryotic model, thus possesses extensive capacity for growth-relevant metabolite exchange and readily cooperates in metabolism within progressively establishing communities.
Keywords	metabolism ; cooperativity ; cellular heterogeneity ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Subject code	612
Language	English
Publishing date	2015-10-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
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