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Thesis defences

PhD Oral Exam - Karamat Mohammad, Biology

Elucidating the Effects of Different Aging-Delaying Interventions on the Cellular Lipidome and Metabolome of Budding Yeast

DATE & TIME
Thursday, July 8, 2021 (all day)
COST

This event is free

ORGANIZATION

School of Graduate Studies

CONTACT

Daniela Ferrer

WHERE

Online

When studying for a doctoral degree (PhD), candidates submit a thesis that provides a critical review of the current state of knowledge of the thesis subject as well as the student’s own contributions to the subject. The distinguishing criterion of doctoral graduate research is a significant and original contribution to knowledge.

Once accepted, the candidate presents the thesis orally. This oral exam is open to the public.

Abstract

In studies presented in this Thesis, I developed novel methods of liquid chromatography coupled with tandem mass spectrometry for the identification and quantitation of the cellular lipidomes and metabolomes of budding yeast. Both these methods are versatile, robust and sensitive. They provide several other advantages over the advanced methods currently employed for the mass spectrometry-based quantitative analyses of cellular lipids and water-soluble metabolites. Using the mass spectrometry-based methods of quantitative lipidomics and metabolomics, I investigated mechanisms through which several aging-delaying (geroprotective) interventions extend the longevity of budding yeast by specifically targeting the metabolism and transport of cellular lipids and water-soluble metabolites. My studies provided evidence that the extract from Salix alba’s bark, called PE21, slows the chronological aging of budding yeast because it lowers the intracellular concentrations of free fatty acids below a toxic threshold. The resulting weakening of an aging-associated liponecrotic form of regulated cell death increases the probability of cell survival during the entire process of chronological aging. My studies suggested two additional mechanisms by which a PE21-dependent reorganization of the cellular lipidome delays the chronological aging of budding yeast. In one of these additional mechanisms, the PE21-dependent rise in the concentrations of endoplasmic reticulum-generated phospholipids activates the pro-longevity process of unfolded protein response in the endoplasmic reticulum. In the other additional mechanism, the PE21-dependent changes in the composition of mitochondrial membrane lipids create a pro-longevity pattern of mitochondrial functionality. I also applied the mass spectrometry-based lipidomics to assess how three different geroprotectors (namely, caloric restriction, tor1Δ mutation and lithocholic acid) influence the lipidomes of quiescent and nonquiescent yeast cells purified using Percoll density gradient centrifugation. My data showed that caloric restriction reorganizes the lipidomes of these cells differently than two other geroprotectors. I proposed two mechanisms by which the caloric restriction-specific lipidome reorganization might slow the chronological aging of quiescent and nonquiescent yeast cells. Moreover, I used my non-targeted metabolomics method to investigate how three different geroprotective interventions (i.e., caloric restriction, tor1Δ mutation and lithocholic acid) affect the intracellular water-soluble metabolome of chronologically aging budding yeast. My findings provide evidence that the three different geroprotectors create distinct metabolic patterns throughout the budding yeast’s entire chronological lifespan. My study identified a distinct metabolic pattern created by the caloric restriction geroprotector. I found two characteristic features that distinguish the caloric restriction-specific metabolic pattern from the cellular metabolism patterns created by the tor1Δ and lithocholic acid geroprotectors. One characteristic feature that distinguishes the caloric restriction-specific metabolic design is its ability to suppress the biosynthesis of methionine, S-adenosylmethionine and cysteine from aspartate, sulfate and 5-methyltetrahydrofolate throughout the chronological lifespan. The other characteristic feature of the caloric restriction-specific metabolic pattern is a decline in the intracellular concentration of ATP, a rise in the intracellular concentrations of AMP and ADP, and an increase in the ADP:ATP and AMP:ATP ratios at various phases of chronological aging.

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