- Author
-
J.C. Chang
- Title
- Soluble adenylyl cyclase
- Subtitle
- A regulator of intrinsic cellular functions
- Supervisors
-
R.P.J. Oude Elferink
A.J. Verhoeven - Co-supervisors
-
C.C. Paulusma
- Award date
- 21 December 2018
- Number of pages
- 259
- ISBN
- 9789402812961
- Document type
- PhD thesis
- Faculty
- Faculty of Medicine (AMC-UvA)
- Abstract
-
Soluble adenylyl cyclase (sAC) is evolutionarily the most conserved member of the mammalian adenylyl cyclases and the only source of cAMP in the cytoplasm and intracellular organelles. Unlike transmembrane adenylyl cyclases (tmACs), sAC activity depends on the local concentrations of ATP, bicarbonate and free Ca2+. On the basis of these distinct features, I investigate the roles of sAC in pH regulation, cellular bioenergetics, and apoptosis.
Bicarbonate transport by the anion exchanger 2 (AE2) is essential in regulation of intracellular pH. The depletion of AE2 leads to bicarbonate retention and induces sAC expression and activity. In murine fibroblasts, knockout of AE2 and high extracellular pH both down-regulate the expression of carbonic anhydrase 2. In primary biliary cholangitis, AE2 is down-regulated in cholangiocytes. Also, in H69 cholangiocytes depletion of AE2 induces sAC expression and, in addition, aggravates bile salt-induced apoptosis, which can be reversed by genetic or pharmacological suppression of sAC.
Suppression of sAC activity elicits a Warburg-like metabolic phenotype, characterized by an elevated cytosolic NADH/NAD+ ratio, enhanced glycolysis, and reduced oxidative phosphorylation. Remarkably, the reprogramming of cellular bioenergetics by sAC is coupled to its regulation of oxidative stress-induced apoptosis. High cytosolic NADH/NAD+ ratios protect against oxidative stress-induced apoptosis while low cytosolic NADH/NAD+ ratios sensitizes cells to apoptosis. Importantly, sAC-dependent cAMP and tmACs-dependent cAMP have opposite effect on both glycogen homeostasis and apoptosis.
Taken together, the present work establishes sAC as a regulator of cellular bioenergetics, metabolism, and apoptosis and suggests that sAC is a potential therapeutic target in cholangiopathies and cancer. - Persistent Identifier
- https://hdl.handle.net/11245.1/4cc43e3d-d4f1-4232-baaf-3ab5ba8c90d2
- Downloads
-
Thesis (complete)
Front matter
Chapter 1: An introduction to the study of soluble adenylyl cyclase with a historic account
Chapter 2: Role of the bicarbonate-responsive soluble adenylyl cyclase in pH sensing and metabolic regulation
Chapter 3: Cyclic AMP and alkaline pH downregulate carbonic anhydrase 2 in mouse fibroblasts
Chapter 4: Soluble adenylyl cyclase is a metabolic switch between aerobic glycolysis and oxidative phosphorylation
Chapter 5: Role of the bicarbonate-responsive soluble adenylyl cyclase in cholangiocyte apoptosis in primary biliary cholangitis: A new hypothesis
Chapter 6: Soluble adenylyl cyclase regulates bile salt-induced apoptosis in human cholangiocytes
Chapter 7: A Warburg-like metabolic phenotype protects against oxidative stress-induced apoptosis: Regulation by the cytosolic NADH/NAD+ redox state
Chapter 8: Improved oxygenation dramatically alters metabolism and gene expression in cultured primary mouse hepatocytes
Chapter 9: General discussion, perspectives, and concluding remarks
English summary; Nederlandse samenvatting; Portfolio; List of publications
Propositions
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