@article{HeilingKnuttiScherretal.2021,
  author    = {Heiling, Sven and Knutti, Nadine and Scherr, Franziska and Geiger, J{\"o}rg and Weikert, Juliane and Rose, Michael and Jahns, Roland and Ceglarek, Uta and Scherag, Andr{\´e} and Kiehntopf, Michael},
  title     = {Metabolite ratios as quality indicators for pre-analytical variation in serum and EDTA plasma},
  series = {Metabolites},
  volume    = {11},
  journal   = {Metabolites},
  number    = {9},
  issn      = {2218-1989},
  doi       = {10.3390/metabo11090638},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-246261},
  year      = {2021},
  abstract  = {In clinical diagnostics and research, blood samples are one of the most frequently used materials. Nevertheless, exploring the chemical composition of human plasma and serum is challenging due to the highly dynamic influence of pre-analytical variation. A prominent example is the variability in pre-centrifugation delay (time-to-centrifugation; TTC). Quality indicators (QI) reflecting sample TTC are of utmost importance in assessing sample history and resulting sample quality, which is essential for accurate diagnostics and conclusive, reproducible research. In the present study, we subjected human blood to varying TTCs at room temperature prior to processing for plasma or serum preparation. Potential sample QIs were identified by Ultra high pressure liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) based metabolite profiling in samples from healthy volunteers (n = 10). Selected QIs were validated by a targeted MS/MS approach in two independent sets of samples from patients (n = 40 and n = 70). In serum, the hypoxanthine/guanosine (HG) and hypoxanthine/inosine (HI) ratios demonstrated high diagnostic performance (Sensitivity/Specificity > 80\%) for the discrimination of samples with a TTC > 1 h. We identified several eicosanoids, such as 12-HETE, 15-(S)-HETE, 8-(S)-HETE, 12-oxo-HETE, (±)13-HODE and 12-(S)-HEPE as QIs for a pre-centrifugation delay > 2 h. 12-HETE, 12-oxo-HETE, 8-(S)-HETE, and 12-(S)-HEPE, and the HI- and HG-ratios could be validated in patient samples.},
  language  = {en}
}
@article{KayvanpourWisdomLackneretal.2022,
  author    = {Kayvanpour, Elham and Wisdom, Michael and Lackner, Maximilian K. and Sedaghat-Hamedani, Farbod and Boeckel, Jes-Niels and M{\"u}ller, Marion and Eghbalian, Rose and Dudek, Jan and Doroudgar, Shirin and Maack, Christoph and Frey, Norbert and Meder, Benjamin},
  title     = {VARS2 depletion leads to activation of the integrated stress response and disruptions in mitochondrial fatty acid oxidation},
  series = {International Journal of Molecular Sciences},
  volume    = {23},
  journal   = {International Journal of Molecular Sciences},
  number    = {13},
  issn      = {1422-0067},
  doi       = {10.3390/ijms23137327},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284590},
  year      = {2022},
  abstract  = {Mutations in mitochondrial aminoacyl-tRNA synthetases (mtARSs) have been reported in patients with mitochondriopathies: most commonly encephalopathy, but also cardiomyopathy. Through a GWAS, we showed possible associations between mitochondrial valyl-tRNA synthetase (VARS2) dysregulations and non-ischemic cardiomyopathy. We aimed to investigate the possible consequences of VARS2 depletion in zebrafish and cultured HEK293A cells. Transient VARS2 loss-of-function was induced in zebrafish embryos using Morpholinos. The enzymatic activity of VARS2 was measured in VARS2-depleted cells via northern blot. Heterozygous VARS2 knockout was established in HEK293A cells using CRISPR/Cas9 technology. BN-PAGE and SDS-PAGE were used to investigate electron transport chain (ETC) complexes, and the oxygen consumption rate and extracellular acidification rate were measured using a Seahorse XFe96 Analyzer. The activation of the integrated stress response (ISR) and possible disruptions in mitochondrial fatty acid oxidation (FAO) were explored using RT-qPCR and western blot. Zebrafish embryos with transient VARS2 loss-of-function showed features of heart failure as well as indications of CNS and skeletal muscle involvements. The enzymatic activity of VARS2 was significantly reduced in VARS2-depleted cells. Heterozygous VARS2-knockout cells showed a rearrangement of ETC complexes in favor of complexes III\(_2\), III\(_2\) + IV, and supercomplexes without significant respiratory chain deficiencies. These cells also showed the enhanced activation of the ISR, as indicated by increased eIF-2α phosphorylation and a significant increase in the transcript levels of ATF4, ATF5, and DDIT3 (CHOP), as well as disruptions in FAO. The activation of the ISR and disruptions in mitochondrial FAO may underlie the adaptive changes in VARS2-depleted cells.},
  language  = {en}
}