UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Mitochondrial and potassium channel dysfunction in pulmonary arterial hypertension

Abu-Hanna, Jeries H.J.; (2020) Mitochondrial and potassium channel dysfunction in pulmonary arterial hypertension. Doctoral thesis (Ph.D), UCL (University College London). Green open access

[thumbnail of Final Thesis - Jeries Abu-Hanna.pdf]
Final Thesis - Jeries Abu-Hanna.pdf

Download (23MB) | Preview


Pulmonary arterial hypertension (PAH) is a rare, progressive and potentially fatal cardiopulmonary disorder, characterised by extensive remodelling and luminal narrowing of the small pulmonary arteries. Central to this remodelling is the proliferation of pulmonary arterial smooth muscle cells (PASMCs) within the medial layers of these arteries. Underlying the proliferative phenotype of PASMCs in PAH is mitochondrial dysfunction and the recently proposed metabolic theory of PAH posits that several, unrelated molecular abnormalities converge to either cause or promote this mitochondrial dysfunction. Moreover, loss of function of potassium (K+) channels, particularly TWIK-related acid-sensitive K+ channel 1 (TASK-1), is also thought to contribute to this abnormal PASMC phenotype and thereby the remodeling process in PAH. This thesis therefore aimed to explore this mitochondrial and K+ channel dysfunction in PASMCs from patients with PAH to aid in the identification of novel therapeutic targets for this disease. In Chapter 3, excessive mitochondrial fragmentation was reported in PAH PASMCs. Increased protein expression and activating phosphorylation of the primary fission mediator dynamin-related protein 1 (DRP1) were found to underlie this increased mitochondrial fission in PAH PASMCs. Moreover, mitochondrial fission 1, which recruits DRP1 to sites of mitochondrial fission was upregulated in PAH PASMCs. Increased proteolytic cleavage and resultant inactivation of the inner mitochondrial fusion protein optic atrophy 1 was also observed in PAH PASMCs. Finally, IP or EP2 prostanoid receptor agonism coupled with protein kinase A activation attenuated mitochondrial fission in PAH PASMCs by inhibiting the activating phosphorylation of DRP1 whilst inducing its inhibitory phosphorylation. In Chapter 4, glucose flux through glycolysis was found to be markedly elevated in PAH PASMCs. Phosphofructokinase-1 (PFK1) catalyses the first rate-limiting step in glycolysis and is positively regulated by 6-phosphofructo-2-kinase/fructose-2,6-bisphophatase 3 (PFKFB3). Increased expression of the muscle (PFKM) and liver (PFKL) isoforms of PFK1 and PFKFB3 was found to underlie the increased glycolytic flux in PAH PASMCs. The step that generates the glycolysis end-product pyruvate is catalysed by pyruvate kinase, namely the muscle isoform (PKM). Reduced PKM activity in PAH PASMCs was implied by an increase in the ratio of the less active splice variant PKM2 to the more active splice variant PKM1, allowing the accumulation of glycolysis intermediates and their spillover into biosynthetic pathways, predominantly the pentose phosphate shunt (PPS). Interestingly, increased protein expression of the PPS rate-limiting enzyme glucose-6-phosphate dehydrogenase was reported in PAH PASMCs in this thesis, suggesting increased glucose shunting into the PPS. In Chapter 5, mitochondrial respiration and ATP production were found to be increased in PAH PASMCs. This is contrary to previous findings and may reflect the metabolic heterogeneity among PAH patients. Underlying this increase in mitochondrial respiration was an increase in mitochondrial mass as a result of an increase in mitochondrial biogenesis coupled with a decrease in mitophagic flux. Accompanying this increase in mitochondrial respiration was an increase in the cellular production of reactive oxygen species (ROS) in PAH PASMCs. Reduced mitochondrial ROS scavenging as a result of the reduced protein expression of superoxide dismutase 2 was also reported in PAH PASMCs as well as an increase in the cytosolic ROS generator 5-lipoxygenase. In Chapter 6, evidence was provided in support of TASK-1 channel dysfunction in PAH PASMCs and a role for this dysfunction in PAH pathogenesis. A trend towards a decrease in TASK-1 expression in PAH PASMCs was observed. In contrast to control PASMCs, TASK-1 channel blockade failed to promote the proliferation of PAH PASMCs. TASK-1 channel blockade was also found to inhibit mitochondrial respiration in control PASMCs, conferring a PAH metabolic phenotype on these cells. The anti-proliferative effects of different prostacyclin mimetics exhibited varying degrees of sensitivity to TASK-1 channel blockade. Finally, TASK-1 channel blockade promoted the apoptosis of pulmonary arterial endothelial cells, an early event in PAH pathogenesis. In conclusion, this thesis provided evidence in support of alterations in mitochondrial and TASK-1 channel function in PAH.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Mitochondrial and potassium channel dysfunction in pulmonary arterial hypertension
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2020. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci
URI: https://discovery.ucl.ac.uk/id/eprint/10102590
Downloads since deposit
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item