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Kayvanpour, Elham [Verfasser:in]; Wisdom, Michael [Verfasser:in]; Lackner, Maximilian K. [Verfasser:in]; Sedaghat-Hamedani, Farbod [Verfasser:in]; Boeckel, Jes-Niels [Verfasser:in]; Müller, Marion [Verfasser:in]; Eghbalian, Rose [Verfasser:in]; Dudek, Jan [Verfasser:in]; Doroudgar, Shirin [Verfasser:in]; Maack, Christoph [Verfasser:in]; Frey, Norbert [Verfasser:in]; Meder, Benjamin [Verfasser:in]

VARS2 Depletion Leads to Activation of the Integrated Stress Response and Disruptions in Mitochondrial Fatty Acid Oxidation

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  • Medientyp: E-Artikel
  • Titel: VARS2 Depletion Leads to Activation of the Integrated Stress Response and Disruptions in Mitochondrial Fatty Acid Oxidation
  • Beteiligte: Kayvanpour, Elham [Verfasser:in]; Wisdom, Michael [Verfasser:in]; Lackner, Maximilian K. [Verfasser:in]; Sedaghat-Hamedani, Farbod [Verfasser:in]; Boeckel, Jes-Niels [Verfasser:in]; Müller, Marion [Verfasser:in]; Eghbalian, Rose [Verfasser:in]; Dudek, Jan [Verfasser:in]; Doroudgar, Shirin [Verfasser:in]; Maack, Christoph [Verfasser:in]; Frey, Norbert [Verfasser:in]; Meder, Benjamin [Verfasser:in]
  • Erschienen: Basel: MDPI, [2024]
  • Erschienen in: International Journal of Molecular Sciences ; 23, (2022)
  • Sprache: Englisch
  • Schlagwörter: heart failure ; VARS2 ; integrated stress response ; mitochondrial FAO
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: Mutations in mitochondrial aminoacyl-tRNA synthetases (mtARSs) have been reportedin 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 possibleconsequences of VARS2 depletion in zebrafish and cultured HEK293A cells. Transient VARS2 loss-offunctionwas induced in zebrafish embryos using Morpholinos. The enzymatic activity of VARS2was measured in VARS2-depleted cells via northern blot. Heterozygous VARS2 knockout wasestablished in HEK293A cells using CRISPR/Cas9 technology. BN-PAGE and SDS-PAGE were usedto investigate electron transport chain (ETC) complexes, and the oxygen consumption rate andextracellular acidification rate were measured using a Seahorse XFe96 Analyzer. The activation ofthe 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 VARS2loss-of-function showed features of heart failure as well as indications of CNS and skeletal muscleinvolvements. The enzymatic activity of VARS2 was significantly reduced in VARS2-depletedcells. Heterozygous VARS2-knockout cells showed a rearrangement of ETC complexes in favor ofcomplexes III2, III2 + IV, and supercomplexes without significant respiratory chain deficiencies. Thesecells also showed the enhanced activation of the ISR, as indicated by increased eIF-2 phosphorylationand a significant increase in the transcript levels of ATF4, ATF5, and DDIT3 (CHOP), as well asdisruptions in FAO. The activation of the ISR and disruptions in mitochondrial FAO may underliethe adaptive changes in VARS2-depleted cells.
  • Zugangsstatus: Freier Zugang
  • Rechte-/Nutzungshinweise: Namensnennung (CC BY)