@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}
}
@article{SchwemmleinMaackBertero2022,
  author    = {Schwemmlein, Julia and Maack, Christoph and Bertero, Edoardo},
  title     = {Mitochondria as therapeutic targets in heart failure},
  series = {Current Heart Failure Reports},
  volume    = {19},
  journal   = {Current Heart Failure Reports},
  number    = {2},
  doi       = {10.1007/s11897-022-00539-0},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324015},
  pages     = {27-37},
  year      = {2022},
  abstract  = {Purpose of Review We review therapeutic approaches aimed at restoring function of the failing heart by targeting mitochondrial reactive oxygen species (ROS), ion handling, and substrate utilization for adenosine triphosphate (ATP) production. Recent Findings Mitochondria-targeted therapies have been tested in animal models of and humans with heart failure (HF). Cardiac benefits of sodium/glucose cotransporter 2 inhibitors might be partly explained by their effects on ion handling and metabolism of cardiac myocytes. Summary The large energy requirements of the heart are met by oxidative phosphorylation in mitochondria, which is tightly regulated by the turnover of ATP that fuels cardiac contraction and relaxation. In heart failure (HF), this mechano-energetic coupling is disrupted, leading to bioenergetic mismatch and production of ROS that drive the progression of cardiac dysfunction. Furthermore, HF is accompanied by changes in substrate uptake and oxidation that are considered detrimental for mitochondrial oxidative metabolism and negatively affect cardiac efficiency. Mitochondria lie at the crossroads of metabolic and energetic dysfunction in HF and represent ideal therapeutic targets.},
  language  = {en}
}