Dr. med. Daniel Heinrich Pfaff

@article{pmid34838714,

title = {The activity of glyoxylase 1 is regulated by glucose-responsive phosphorylation on Tyr136},

author = {Fabiola Garcia Cortizo and Daniel Pfaff and Angela Wirth and Andrea Schlotterer and Rebekka Medert and Jakob Morgenstern and Tobias Weber and Hans-Peter Hammes and Thomas Fleming and Peter Paul Nawroth and Marc Freichel and Aurelio A Teleman},

doi = {10.1016/j.molmet.2021.101406},

issn = {2212-8778},

year  = {2022},

date = {2022-01-01},

journal = {Mol Metab},

volume = {55},

pages = {101406},

abstract = {OBJECTIVE: Methylglyoxal (MG) is a highly reactive α-oxoaldehyde that glycates proteins. MG has been linked to the development of diabetic complications: MG is the major precursor of advanced glycation end products (AGEs), a risk marker for diabetic complications in humans. Furthermore, flies and fish with elevated MG develop insulin resistance, obesity, and hyperglycemia. MG is detoxified in large part through the glyoxalase system, whose rate-limiting enzyme is glyoxalase I (Glo1). Hence, we aimed to study how Glo1 activity is regulated.



METHODS: We studied the regulation and effect of post-translational modifications of Glo1 in tissue culture and in mouse models of diabetes.



RESULTS: We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. We find that Glo1 Y136 phosphorylation responds in a bimodal fashion to glucose levels, increasing in cell culture from 0 mM to 5 mM (physiological) glucose, and then decreasing at higher glucose concentrations, both in cell culture and in mouse models of hyperglycemia.



CONCLUSIONS: These data, together with published findings that elevated MG leads to hyperglycemia, suggest the existence of a deleterious positive feedback loop whereby hyperglycemia leads to reduced Glo1 activity, contributing to elevated MG levels, which in turn promote hyperglycemia. Hence, perturbations elevating either glucose or MG have the potential to start an auto-amplifying feedback loop contributing to diabetic complications.},

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pubstate = {published},

tppubtype = {article}

}

@article{pmid29421830,

title = {Effects of the Reactive Metabolite Methylglyoxal on Cellular Signalling, Insulin Action and Metabolism - What We Know in Mammals and What We Can Learn From Yeast},

author = {Johanna Zemva and Daniel Pfaff and Jan B Groener and Thomas Fleming and Stephan Herzig and Aurelio Teleman and Peter P Nawroth and Jens Tyedmers},

doi = {10.1055/s-0043-122382},

issn = {1439-3646},

year  = {2019},

date = {2019-04-01},

journal = {Exp Clin Endocrinol Diabetes},

volume = {127},

number = {4},

pages = {203--214},

abstract = {Levels of reactive metabolites such as reactive carbonyl and oxygen species are increased in patients with diabetes mellitus. The most important reactive dicarbonyl species, methylglyoxal (MG), formed as by-product during glucose metabolism, is more and more recognized as a trigger for the development and progression of diabetic complications. Although it is clear that MG provokes toxic effects, it is currently not well understood what cellular changes MG induces on a molecular level that may lead to pathophysiological conditions found in long-term diabetic complications. Here we review the current knowledge about the molecular effects that MG can induce in a cell. Within the mammalian system, we will focus mostly on the metabolic effects MG exerts when applied systemically to rodents or when applied  to pancreatic β-cells and adipocytes. Due to the common limitations associated with complex model organisms, we then summarize how yeast as a very simple model organism can help to gain valuable comprehensive information on general defence pathways cells exert in response to MG stress. Pioneering studies in additional rather simple eukaryotic model organisms suggest that many cellular reactions in response to MG are highly conserved throughout evolution.},

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pubstate = {published},

tppubtype = {article}

}

@article{pmid30087348,

title = {Dietary stearic acid regulates mitochondria in vivo in humans},

author = {Deniz Senyilmaz-Tiebe and Daniel H Pfaff and Sam Virtue and Kathrin V Schwarz and Thomas Fleming and Sandro Altamura and Martina U Muckenthaler and Jürgen G Okun and Antonio Vidal-Puig and Peter Nawroth and Aurelio A Teleman},

doi = {10.1038/s41467-018-05614-6},

issn = {2041-1723},

year  = {2018},

date = {2018-08-01},

journal = {Nat Commun},

volume = {9},

number = {1},

pages = {3129},

abstract = {Since modern foods are unnaturally enriched in single metabolites, it is important to understand which metabolites are sensed by the human body and which are not. We previously showed that the fatty acid stearic acid (C18:0) signals via a dedicated pathway to regulate mitofusin activity and thereby mitochondrial morphology and function in cell culture. Whether this pathway is poised to sense changes in dietary intake of C18:0 in humans is not known. We show here that C18:0 ingestion rapidly and robustly causes mitochondrial fusion in people within 3 h after ingestion. C18:0 intake also causes a drop in circulating long-chain acylcarnitines, suggesting increased fatty acid beta-oxidation in vivo. This work thereby identifies C18:0 as a dietary metabolite that is sensed by our bodies to control our mitochondria. This could explain part of the epidemiological differences between C16:0 and C18:0, whereby C16:0 increases cardiovascular and cancer risk whereas C18:0 decreases both.},

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pubstate = {published},

tppubtype = {article}

}

@article{pmid29551588,

title = {Elevated Levels of the Reactive Metabolite Methylglyoxal Recapitulate Progression of Type 2 Diabetes},

author = {Alexandra Moraru and Janica Wiederstein and Daniel Pfaff and Thomas Fleming and Aubry K Miller and Peter Nawroth and Aurelio A Teleman},

doi = {10.1016/j.cmet.2018.02.003},

issn = {1932-7420},

year  = {2018},

date = {2018-04-01},

journal = {Cell Metab},

volume = {27},

number = {4},

pages = {926--934.e8},

abstract = {The molecular causes of type 2 diabetes (T2D) are not well understood. Both type 1 diabetes (T1D) and T2D are characterized by impaired insulin signaling and hyperglycemia. From analogy to T1D, insulin resistance and hyperglycemia are thought to also play causal roles in T2D. Recent clinical studies, however, found that T2D patients treated to maintain glycemia below the diabetes definition threshold (HbA < 6.5%) still develop diabetic complications. This suggests additional insulin- and glucose-independent mechanisms could be involved in T2D progression and/or initiation. T2D patients have elevated levels of the metabolite methylglyoxal (MG). We show here, using Drosophila glyoxalase 1 knockouts, that animals with elevated methylglyoxal recapitulate several core aspects of T2D: insulin resistance, obesity, and hyperglycemia. Thus elevated MG could constitute one root cause of T2D, suggesting that the molecular causes of elevated MG warrant further study.},

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pubstate = {published},

tppubtype = {article}

}

@article{pmid28778882,

title = {Reply to Richarme: Evidence against a role of DJ-1 in methylglyoxal detoxification},

author = {Daniel H Pfaff and Thomas Fleming and Peter Nawroth and Aurelio A Teleman},

doi = {10.1074/jbc.L117.798579},

issn = {1083-351X},

year  = {2017},

date = {2017-08-01},

journal = {J Biol Chem},

volume = {292},

number = {31},

pages = {12784--12785},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid27903648,

title = {Evidence Against a Role for the Parkinsonism-associated Protein DJ-1 in Methylglyoxal Detoxification},

author = {Daniel H Pfaff and Thomas Fleming and Peter Nawroth and Aurelio A Teleman},

doi = {10.1074/jbc.M116.743823},

issn = {1083-351X},

year  = {2017},

date = {2017-01-01},

journal = {J Biol Chem},

volume = {292},

number = {2},

pages = {685--690},

abstract = {Methylglyoxal (MG) is a reactive metabolite that forms adducts on cysteine, lysine and arginine residues of proteins, thereby affecting their function. Methylglyoxal is detoxified by the Glyoxalase system, consisting of two enzymes, Glo1 and Glo2, that act sequentially to convert MG into d-lactate. Recently, the Parkinsonism-associated protein DJ-1 was described in vitro to have glyoxalase activity, thereby detoxifying the MG metabolite, or deglycase activity, thereby removing the adduct formed by MG on proteins. Since Drosophila is an established model system to study signaling, neurodegeneration, and metabolic regulation in vivo, we asked whether DJ-1 contributes to MG detoxification in vivo Using both DJ-1 knockdown in Drosophila cells in culture, and DJ-1β knock-out flies, we could detect no contribution of DJ-1 to survival to MG challenge or to accumulation of MG protein adducts. Furthermore, we provide data suggesting that the previously reported deglycation activity of DJ-1 can be ascribed to a TRIS buffer artifact.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid23576680,

title = {Fine-tuning of regulatory T cell function: the role of calcium signals and naive regulatory T cells for regulatory T cell deficiency in multiple sclerosis},

author = {Alexander Schwarz and Marijana Schumacher and Daniel Pfaff and Kai Schumacher and Sven Jarius and Bettina Balint and Heinz Wiendl and Jürgen Haas and Brigitte Wildemann},

doi = {10.4049/jimmunol.1203224},

issn = {1550-6606},

year  = {2013},

date = {2013-05-01},

journal = {J Immunol},

volume = {190},

number = {10},

pages = {4965--4970},

abstract = {The suppressor function of regulatory T cells (Tregs) is impaired in multiple sclerosis (MS), but the mechanisms underlying this deficiency are not fully understood. As Tregs counteract the sustained elevation of intracellular calcium, which is indispensable for full activation of conventional T cells (Tcons), we hypothesized that interference with this pathway might prompt MS-related Treg dysfunction. Using single-cell live imaging, we observed that Tregs rapidly reduce Ca(2+) influx and downstream signals in Tcons upon cell contact, yet differ in their potency to efficiently suppress several target cells at the same time. Strikingly, individual Tregs harboring a CD4(+)CD25(+)FOXP3(+)CD45RA(+) naive phenotype suppressed significantly more adjacent Tcons than did CD4(+)CD25(+)FOXP3(+)CD45RA(-) memory Tregs. Some constituents even completely failed to dampen Tcon Ca(2+) influx and were contained exclusively in the memory subset. In accordance with their more powerful suppressive performance, the Ca(2+) signature was considerably enhanced in naive Tregs in response to TCR triggering, compared with the memory counterparts. MS Tregs displayed a significantly diminished suppression of mean Ca(2+) influx in the sum of individual Tcons recorded. This reduced inhibitory activity was closely linked to decreased numbers of individual Tcons becoming suppressed by adjacent Tregs and, in turn, correlated with a marked reduction of naive subtypes and concomitant expansion of nonsuppressive memory phenotypes. We conclude that the superior achievement of naive Tregs is pivotal in maintaining Treg efficiency. As a consequence, MS Tregs become defective because they lack naive subtypes and are disproportionately enriched in memory cells that have lost their inherent downregulatory activity.},

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pubstate = {published},

tppubtype = {article}

}