Disease-linked lysine glutarylation impairs function and interactions of mitochondrial proteins and contribute to mitochondrial heterogeneity

ABSTRACT: Inherited deficiencies of the lysine and tryptophan catabolic pathways, due to mutations in the glutaryl-CoA-dehydrogenase (GCDH) gene, cause glutaric aciduria type 1 (GA1). In mammals two metabolic routes for L-lysine oxidation exist, the mitochondrial saccharopine pathway, which is predominant in extracerebral tissue and the peroxysomal/cytosolic pipecolate pathway, the main pathway in adult brain. A unique feature of all pathways is the formation of glutaryl-CoA that is converted into crotonyl-CoA via GCDH. In this study we identified increased lysine glutarylation, a novel reversible post-translational modification, in various tissues and cultured cells of Gcdh KO mice as a result of glutaryl-CoA accumulation. Our analysis revealed that glutarylation is widespread in mitochondria. By using a proteomic approach, we identified 37 and 154 glutarylated mitochondrial proteins in brain and liver tissue from Gcdh KO mice, respectively. We further showed that glutarylation supresses glutamate dehydrogenase (GDH) and carbonic anhydrase 5B activity, plus the direct interaction between GCDH and GDH.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Marc Sylvester  

LAB HEAD: Thomas Braulke

PROVIDER: PXD007881 | Pride | 2018-07-11

REPOSITORIES: Pride