Elevated O‐GlcNAcylation levels improve mitochondrial function
In: The FASEB Journal ; volume 30, issue S1 ; ISSN 0892-6638 1530-6860, 2016
academicJournal
Zugriff:
O‐linked N ‐acetylglucosamine (O‐GlcNAc) is a highly dynamic post‐translational modification that involves an addition of a single N‐ acetylglucosamine to serine and threonine residue in mitochondria, nuclear and cytoplasmic proteins. O‐GlcNAc cycling is the addition and removal of O‐GlcNAc by O‐GlcNAc transferase (OGT) and O‐GlcNAcase (OGA) respectively. Disruptions in O‐GlcNAc cycling contribute to diseases such as diabetes, cancer, and neurodegeneration. Accumulative dysfunctional mitochondria can also lead to the development of neurodegenerative diseases, and importantly, O‐GlcNAcylation regulates mitochondrial function. Previously, using a proteomics based screen we found that altering the expression of OGT and OGA disrupted mitochondrial protein expression, including proteins involved in the respiratory chain and TCA cycle. Furthermore, mitochondrial morphology in the over‐expressing cells had reduced and disorganized cristae and altered shape and size. Both cellular respiration and glycolysis was impaired in the OGT/OGA gain of function cells. These data suggested that O‐GlcNAc cycling was essential for the proper regulation of mitochondrial function. We hypothesized that prolonged elevations in cellular O‐GlcNAc levels would alter the metabolic profile of the cell. We disrupted O‐GlcNAc cycling by either treating SH‐SY5Y neuroblastoma cells with low levels of Glucosamine (GlcN) or OGA inhibitor Thiamet‐G (TMG). Importantly, the metabolic substrate for O‐GlcNAcylation is UDP‐GlcNAc. UDP‐GlcNAc is synthesized via the hexosamine biosynthetic pathway, which is highly sensitive towards the availability of nutrients in the cellular environment. GlcN feeds into the hexosamine biosynthetic pathway after the first rate‐limiting enzyme GFAT1, glutamine fructose‐6‐phosphate aminotransferase 1, and additional supplementation of GlcN increases O‐GlcNAcylation via elevating the synthesis of UDP‐GlcNAc. We found that prolonged TMG/GlcN treatment improved mitochondrial function. In the TMG/GlcN treated cells, reactive ...
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Elevated O‐GlcNAcylation levels improve mitochondrial function
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Autor/in / Beteiligte Person: | Tan, Ee Phie ; Swerdlow, Russell ; Slawson, Chad |
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Zeitschrift: | The FASEB Journal ; volume 30, issue S1 ; ISSN 0892-6638 1530-6860, 2016 |
Veröffentlichung: | Wiley, 2016 |
Medientyp: | academicJournal |
DOI: | 10.1096/fasebj.30.1_supplement.845.1 |
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