The importance of thiol availability to transsulfuration, antioxidant systems and mitochondrial H2S formation in the rat
| dc.contributor.author | Tamanna, Nahid | |
| dc.contributor.examiningcommittee | House, James (Food and Human Nutritional Sciences), Campbell, Kevin (Biological Sciences), Jacobs, Rene (University of Alberta) | en_US |
| dc.contributor.supervisor | Treberg, Jason (Biological Sciences) | en_US |
| dc.date.accessioned | 2019-11-04T20:01:08Z | |
| dc.date.available | 2019-11-04T20:01:08Z | |
| dc.date.issued | 2019-10-02 | en_US |
| dc.date.submitted | 2019-10-02T17:53:05Z | en |
| dc.degree.discipline | Biological Sciences | en_US |
| dc.degree.level | Doctor of Philosophy (Ph.D.) | en_US |
| dc.description.abstract | Sulphur containing amino acids play numerous roles in cellular system including protein synthesis, cell replication, a cellular defence mechanism and energy metabolism. Of the two-major sulphur containing amino acids, methionine is indispensable whereas cysteine is semi-essential considering cysteine can be synthesized from dietary methionine. During the metabolism of methionine, homocysteine is formed as an intermediate which holds a critical position between transsulfuration and transmethylation pathways. Metabolism of homocysteine through transsulfuration leads to the formation of cysteine which serves as a precursor for the major antioxidant glutathione (GSH) or hydrogen sulphide (H2S). A diet low in sulphur amino acids, known as methionine restriction (MR), increases lifespan in diverse species. Unconventional to lifespan extension mechanism, methionine restriction causes hyperhomocysteinemia and decreases tissue GSH levels in rodents. Linking the significance of sulphur amino acids, longevity and H2S, previously it has been proposed that increased H2S production delays the onset of aging and age-related aspects in nutritional restriction diets. Additionally, it has been suggested that the upregulation of transsulfuration pathway produces H2S in MR mice while hyperhomocysteinemia and low tissue GSH in MR animals indicate the opposite. Despite a declination of a major antioxidant GSH, how MR protects the cellular environment from pro-oxidants is not clear. Apart from transsulfuration, H2S can also be produced by the mercaptopyruvate sulfurtransferase (MPST). Along with other functions, H2S is reported to increase mitochondrial respiration rate. To generate H2S in in vitro, MPST require accessory reductant(s) and it is not known whether mitochondria also needs reductant(s) to release H2S which in turn enhances respiration rate. To investigate the link between homocysteine, H2S and GSH, we fed Fischer 344 rats MR and control diets. We found that MR impedes transsulfuration by inhibiting the cystathionine-β-synthase and simultaneously maintains H2S production capacity by enhancing alternate pathways. Methionine restriction increases the activity of thioredoxin reductase and glutathione reductase which can compensate for the low GSH level in cytosol and parallelly reduces reactive oxygen species production in mitochondria presumably by enhancing proton leak. Liver mitochondria assays from Sprague-Dawley rat further suggested that MPST require thioredoxin to enhance mitochondrial bioenergetics. | en_US |
| dc.description.note | February 2020 | en_US |
| dc.identifier.uri | http://hdl.handle.net/1993/34357 | |
| dc.language.iso | eng | en_US |
| dc.rights | open access | en_US |
| dc.subject | Methionine restriction, sulphur amino acid, aging, antioxidant, oxidative stress, mitochondria, H2S | en_US |
| dc.title | The importance of thiol availability to transsulfuration, antioxidant systems and mitochondrial H2S formation in the rat | en_US |
| dc.type | doctoral thesis | en_US |