Loss of succinyl-CoA synthetase in mouse forebrain results in hypersuccinylation with perturbed neuronal transcription and metabolism.

Autor:	Lancaster MS; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Kim B; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Doud EH; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Tate MD; Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Medical Neuroscience Graduate Program, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Sharify AD; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Gao H; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Chen D; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Simpson E; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Gillespie P; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Chu X; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Miller MJ; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Wang Y; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Liu Y; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Mosley AL; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Kim J; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Medical Neuroscience Graduate Program, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Graham BH; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Electronic address: bregraha@iu.edu.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2023 Oct 31; Vol. 42 (10), pp. 113241. Date of Electronic Publication: 2023 Oct 17.
DOI:	10.1016/j.celrep.2023.113241
Abstrakt:	Lysine succinylation is a subtype of protein acylation associated with metabolic regulation of succinyl-CoA in the tricarboxylic acid cycle. Deficiency of succinyl-CoA synthetase (SCS), the tricarboxylic acid cycle enzyme catalyzing the interconversion of succinyl-CoA to succinate, results in mitochondrial encephalomyopathy in humans. This report presents a conditional forebrain-specific knockout (KO) mouse model of Sucla2, the gene encoding the ATP-specific beta isoform of SCS, resulting in postnatal deficiency of the entire SCS complex. Results demonstrate that accumulation of succinyl-CoA in the absence of SCS leads to hypersuccinylation within the murine cerebral cortex. Specifically, increased succinylation is associated with functionally significant reduced activity of respiratory chain complex I and widescale alterations in chromatin landscape and gene expression. Integrative analysis of the transcriptomic data also reveals perturbations in regulatory networks of neuronal transcription in the KO forebrain. Together, these findings provide evidence that protein succinylation plays a significant role in the pathogenesis of SCS deficiency. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu