Loss of succinyl-CoA synthetase in mouse forebrain results in hypersuccinylation with perturbed neuronal transcription and metabolism
Makayla S. Lancaster,
Byungwook Kim,
Emma H. Doud,
Mason D. Tate,
Ahmad D. Sharify,
Hongyu Gao,
Duojiao Chen,
Ed Simpson,
Patrick Gillespie,
Xiaona Chu,
Marcus J. Miller,
Yue Wang,
Yunlong Liu,
Amber L. Mosley,
Jungsu Kim,
Brett H. Graham
Affiliations
Makayla S. Lancaster
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Byungwook Kim
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
Emma H. Doud
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Mason D. Tate
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
Ahmad D. Sharify
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
Hongyu Gao
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
Duojiao Chen
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Ed Simpson
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Patrick Gillespie
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Xiaona Chu
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Marcus J. Miller
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Yue Wang
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Yunlong Liu
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
Amber L. Mosley
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
Jungsu Kim
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
Brett H. Graham
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Corresponding author
Summary: 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.
