Disease-Linked Glutarylation Impairs Function and Interactions of Mitochondrial Proteins and Contributes to Mitochondrial Heterogeneity
Summary: 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 rol...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2018-09-01
|
| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124718312683 |
| _version_ | 1818309231549349888 |
|---|---|
| author | Jessica Schmiesing Stephan Storch Ann-Cathrin Dörfler Michaela Schweizer Georgia Makrypidi-Fraune Melanie Thelen Marc Sylvester Volkmar Gieselmann Catherine Meyer-Schwesinger Friedrich Koch-Nolte Henning Tidow Chris Mühlhausen Abdul Waheed William S. Sly Thomas Braulke |
| author_facet | Jessica Schmiesing Stephan Storch Ann-Cathrin Dörfler Michaela Schweizer Georgia Makrypidi-Fraune Melanie Thelen Marc Sylvester Volkmar Gieselmann Catherine Meyer-Schwesinger Friedrich Koch-Nolte Henning Tidow Chris Mühlhausen Abdul Waheed William S. Sly Thomas Braulke |
| author_sort | Jessica Schmiesing |
| collection | DOAJ |
| description | Summary: 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. : 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. Keywords: glutaryl-CoA-dehydrogenase, glutaryl-proteome, glutamate dehydrogenase, carboanhydrase 5B, protein-protein interaction, immunogold electron microscopy, glutaric aciduria type 1/brain |
| first_indexed | 2024-12-13T07:26:53Z |
| format | Article |
| id | doaj.art-b3476a6f49174f2f967f25a8a25f0543 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-13T07:26:53Z |
| publishDate | 2018-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-b3476a6f49174f2f967f25a8a25f05432022-12-21T23:55:18ZengElsevierCell Reports2211-12472018-09-01241129462956Disease-Linked Glutarylation Impairs Function and Interactions of Mitochondrial Proteins and Contributes to Mitochondrial HeterogeneityJessica Schmiesing0Stephan Storch1Ann-Cathrin Dörfler2Michaela Schweizer3Georgia Makrypidi-Fraune4Melanie Thelen5Marc Sylvester6Volkmar Gieselmann7Catherine Meyer-Schwesinger8Friedrich Koch-Nolte9Henning Tidow10Chris Mühlhausen11Abdul Waheed12William S. Sly13Thomas Braulke14Department of Biochemistry, Children’s Hospital, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, GermanyDepartment of Biochemistry, Children’s Hospital, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, GermanyDepartment of Biochemistry, Children’s Hospital, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, GermanyCenter of Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, GermanyDepartment of Biochemistry, Children’s Hospital, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, GermanyInstitute of Biochemistry and Molecular Biology, University of Bonn, 53115 Bonn, GermanyInstitute of Biochemistry and Molecular Biology, University of Bonn, 53115 Bonn, GermanyInstitute of Biochemistry and Molecular Biology, University of Bonn, 53115 Bonn, GermanyDepartment of Internal Medicine III, Nephrology and Rheumatology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, GermanyInstitute of Immunology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, GermanyThe Hamburg Center for Ultrafast Imaging & Department Chemistry, University Hamburg, 20146 Hamburg, GermanyDepartment of Biochemistry, Children’s Hospital, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, GermanyDepartment of Biochemistry and Molecular Biology, Edward A. Doisy Research Center, Saint Louis University School of Medicine, St. Louis, MO 63104, USADepartment of Biochemistry and Molecular Biology, Edward A. Doisy Research Center, Saint Louis University School of Medicine, St. Louis, MO 63104, USADepartment of Biochemistry, Children’s Hospital, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; Corresponding authorSummary: 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. : 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. Keywords: glutaryl-CoA-dehydrogenase, glutaryl-proteome, glutamate dehydrogenase, carboanhydrase 5B, protein-protein interaction, immunogold electron microscopy, glutaric aciduria type 1/brainhttp://www.sciencedirect.com/science/article/pii/S2211124718312683 |
| spellingShingle | Jessica Schmiesing Stephan Storch Ann-Cathrin Dörfler Michaela Schweizer Georgia Makrypidi-Fraune Melanie Thelen Marc Sylvester Volkmar Gieselmann Catherine Meyer-Schwesinger Friedrich Koch-Nolte Henning Tidow Chris Mühlhausen Abdul Waheed William S. Sly Thomas Braulke Disease-Linked Glutarylation Impairs Function and Interactions of Mitochondrial Proteins and Contributes to Mitochondrial Heterogeneity Cell Reports |
| title | Disease-Linked Glutarylation Impairs Function and Interactions of Mitochondrial Proteins and Contributes to Mitochondrial Heterogeneity |
| title_full | Disease-Linked Glutarylation Impairs Function and Interactions of Mitochondrial Proteins and Contributes to Mitochondrial Heterogeneity |
| title_fullStr | Disease-Linked Glutarylation Impairs Function and Interactions of Mitochondrial Proteins and Contributes to Mitochondrial Heterogeneity |
| title_full_unstemmed | Disease-Linked Glutarylation Impairs Function and Interactions of Mitochondrial Proteins and Contributes to Mitochondrial Heterogeneity |
| title_short | Disease-Linked Glutarylation Impairs Function and Interactions of Mitochondrial Proteins and Contributes to Mitochondrial Heterogeneity |
| title_sort | disease linked glutarylation impairs function and interactions of mitochondrial proteins and contributes to mitochondrial heterogeneity |
| url | http://www.sciencedirect.com/science/article/pii/S2211124718312683 |
| work_keys_str_mv | AT jessicaschmiesing diseaselinkedglutarylationimpairsfunctionandinteractionsofmitochondrialproteinsandcontributestomitochondrialheterogeneity AT stephanstorch diseaselinkedglutarylationimpairsfunctionandinteractionsofmitochondrialproteinsandcontributestomitochondrialheterogeneity AT anncathrindorfler diseaselinkedglutarylationimpairsfunctionandinteractionsofmitochondrialproteinsandcontributestomitochondrialheterogeneity AT michaelaschweizer diseaselinkedglutarylationimpairsfunctionandinteractionsofmitochondrialproteinsandcontributestomitochondrialheterogeneity AT georgiamakrypidifraune diseaselinkedglutarylationimpairsfunctionandinteractionsofmitochondrialproteinsandcontributestomitochondrialheterogeneity AT melaniethelen diseaselinkedglutarylationimpairsfunctionandinteractionsofmitochondrialproteinsandcontributestomitochondrialheterogeneity AT marcsylvester diseaselinkedglutarylationimpairsfunctionandinteractionsofmitochondrialproteinsandcontributestomitochondrialheterogeneity AT volkmargieselmann diseaselinkedglutarylationimpairsfunctionandinteractionsofmitochondrialproteinsandcontributestomitochondrialheterogeneity AT catherinemeyerschwesinger diseaselinkedglutarylationimpairsfunctionandinteractionsofmitochondrialproteinsandcontributestomitochondrialheterogeneity AT friedrichkochnolte diseaselinkedglutarylationimpairsfunctionandinteractionsofmitochondrialproteinsandcontributestomitochondrialheterogeneity AT henningtidow diseaselinkedglutarylationimpairsfunctionandinteractionsofmitochondrialproteinsandcontributestomitochondrialheterogeneity AT chrismuhlhausen diseaselinkedglutarylationimpairsfunctionandinteractionsofmitochondrialproteinsandcontributestomitochondrialheterogeneity AT abdulwaheed diseaselinkedglutarylationimpairsfunctionandinteractionsofmitochondrialproteinsandcontributestomitochondrialheterogeneity AT williamssly diseaselinkedglutarylationimpairsfunctionandinteractionsofmitochondrialproteinsandcontributestomitochondrialheterogeneity AT thomasbraulke diseaselinkedglutarylationimpairsfunctionandinteractionsofmitochondrialproteinsandcontributestomitochondrialheterogeneity |