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Schmiesing, Jessica; Storch, Stephan; Dörfler, Ann-Cathrin; Schweizer, Michaela; Makrypidi-Fraune, Georgia; Thelen, Melanie; Sylvester, Marc; Gieselmann, Volkmar; Meyer-Schwesinger, Catherine; Koch-Nolte, Friedrich; Tidow, Henning; Mühlhausen, Chris; Waheed, Abdul; Sly, William S.; Braulke, Thomas
Cell reports, 09/2018, Letnik: 24, Številka: 11Journal Article
Lysine glutarylation (Kglu) of mitochondrial proteins is associated with glutaryl-CoA dehydrogenase (GCDH) deficiency, which impairs lysine/tryptophan degradation and causes destruction of striatal neurons during catabolic crisis with subsequent movement disability. By investigating the role of Kglu modifications in this disease, we compared the brain and liver glutarylomes of Gcdh-deficient mice. In the brain, we identified 73 Kglu sites on 37 mitochondrial proteins involved in various metabolic degradation pathways. Ultrastructural immunogold studies indicated that glutarylated proteins are heterogeneously distributed in mitochondria, which are exclusively localized in glial cells. In liver cells, all mitochondria contain Kglu-modified proteins. Glutarylation reduces the catalytic activities of the most abundant glutamate dehydrogenase (GDH) and the brain-specific carbonic anhydrase 5b and interferes with GDH-protein interactions. We propose that Kglu contributes to the functional heterogeneity of mitochondria and may metabolically adapt glial cells to the activity and metabolic demands of neighboring GCDH-deficient neurons. Display omitted •Glutaryl-CoA dehydrogenase (GCDH) defects increase mitochondrial glutaryl-CoA level•Glutarylated mitochondrial proteins accumulate in glial cells of GCDH KO mice•Glutarylation suppresses GDH activity and protein interactions•Affected glutamate metabolism links lysine glutarylation with neuronal anaplerosis Schmiesing et al. show that the lack of GCDH results in glutarylation of mitochondrial proteins in glial cells affecting amino acid metabolism and the tricarboxylic acid cycle. They identify glutamate dehydrogenase as a target suppressed by glutarylation that is linked to glial glutamate metabolism and anaplerosis in GCDH-deficient neuronal cells.
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