University of Cambridge
Regulation of Mitochondrial Function by Histone Acetylation and Mitochondrial Acetyl-CoA Levels in Saccharomyces cerevisiae
Abstract
dc:description.abstractPrevious studies from our lab demonstrated that starvation signals transmitted by multiple kinases, including the PAS kinase Rim15, the DYRK kinase Yak1, the GSK-3 homologue Mck1 and the energy-sensing SNF1 complex, were converged to regulate starvation-induced expression of molecular chaperones, metabolic reprogramming to accumulate storage carbohydrates, activation of antioxidant defence systems, and ultimately the extension of chronological lifespan. These starvation-induced phenotypes were at least partially mediated by three classes of transcription factors (TFs), including the general stress response factors Msn2/4, the post-diauxic shift factor Gis1 and the heat-shock factor Hsf1. In the first result chapter, the contribution of the three classes of TFs to the expression of chaperone reporters, antioxidant defence systems, storage carbohydrate accumulation, and chronological lifespan (CLS) extension were assessed. While Hsf1 played a marginal role in the above starvation-induced phenotypes, Gis1 and Msn2/4 were the major regulators of metabolic reprogramming and stress resistance. Furthermore, the activation of the antioxidant defence systems was predominantly mediated by Msn2/4 in starving cells. Recent genome-wide screening identified several mutants displaying significantly enhanced levels of both chaperone reporters (pHSP26-HSP26-RFP and pSSA3-RFP), including the mutants of the HDA1 histone deacetylase (HDAC) complex, suggesting the involvement of histone acetylation in the regulation of starvation-induced gene expression. In the second result chapter, the HDA1 complex was found to be the only HDAC in yeast that acts to restrain the expression of the starvation-induced chaperone reporters, in a manner dependent on Gcn5, a histone acetyltransferase (HAT). Subsequent genetic and transcriptome analyses indicated that Gcn5 functions in the HAT module of the SAGA complex to regulate mitochondrial function and respiratory growth by promoting the TCA cycle, the oxidative phosphorylation pathway, and also the antioxidant defence systems. Phenotypic analyses indicated that histone acetylation by Gcn5 contributes to metabolic reprogramming and chronological lifespan extension. In the final result chapter, the mitochondrial fatty acid synthesis (mtFAS) pathway was found to be responsible for mitochondrial genome maintenance. Preliminary genetic analyses suggested that iron-citrate toxicity may account for mitochondrial genome loss in mtFAS mutants. Put together, these findings suggest that the energy levels in the form of acetyl-CoA are spatially coordinated to ensure mitochondrial biogenesis, respiratory cell growth and long-term cell survival.
Degree
thesis:*- Name dc:type.qualificationname
- Doctor of Philosophy (PhD)
- Level dc:type.qualificationlevel
- Doctoral
- Grantor dc:publisher.institution
- University of Cambridge
- Year dc:date.issued
- 2021
Author and committee
dc:creator, dc:contributor.*- Author dc:creator
-
- Li, Kaiqiang
- Advisors dc:contributor.advisor
-
- Zhang, Nianshu
- Griffin, Julian
Subjects
dc:subject × 7Rights
dc:rightsIdentifiers
dc:identifier.*- DOI dc:identifier.doi
- https://doi.org/10.17863/CAM.76193
- OAI identifier oai:identifier
- oai:www.repository.cam.ac.uk:1810/328745