Link to the University of Pittsburgh Homepage
Link to the University Library System Homepage Link to the Contact Us Form

Frataxin deficiency coordinates iron-sulfur-dependent metabolic and genomic stress to promote endothelial senescence in pulmonary hypertension

Culley, Miranda (2020) Frataxin deficiency coordinates iron-sulfur-dependent metabolic and genomic stress to promote endothelial senescence in pulmonary hypertension. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

Download (4MB) | Preview


Pulmonary hypertension (PH) is a heterogeneous, fatal disease of the lung vasculature with incompletely defined molecular underpinnings. Specifically, the pathological contributions of endothelial cells to this panvasculopathy remain controversial and unresolved. Endothelial mitochondrial dysfunction and DNA damage have been separately linked to PH, but any shared mechanistic regulation, joint contribution to shifting endothelial phenotypes, and relevance across PH subtypes are unknown. Mutations in the iron-sulfur (Fe-S) biogenesis gene frataxin (FXN) disrupt metabolism and genomic integrity, causing Friedreich’s ataxia (FRDA). This multisystem disease is defined by neurodegeneration and hypertrophic cardiomyopathy (HCM) with the latter driving patient mortality. HCM is often complicated by PH but few studies have interrogated pulmonary vascular phenotypes in FRDA. Separately, deficiencies of other Fe-S cluster assembly genes induced endothelial mitochondrial dysfunction and PH development in vivo. Therefore, we hypothesized that endothelial FXN deficiency and its metabolic and genomic consequences may predispose to PH. Here, we demonstrated acute FXN knockdown abrogated Fe-S biogenesis to attenuate mitochondrial respiration and induce replication stress and growth arrest. Sustained FXN deficiency led to inhibition of Fe-S-containing nuclear proteins, persistent DNA damage response, and apoptosis resistance, culminating in increased vasomotor tone and senescence. Consequently, endothelial FXN deficiency in hypoxic mice increased senescence and worsened PH, which could be prevented with senolytic treatment. Supporting this mechanism, reduced FXN expression alongside elevated senescence markers were observed in animal and patient lung tissues representing multiple PH etiologies. Specifically, we defined HIF--dependent epigenetic reduction of FXN, illustrating the relevance of acquired FXN deficiency in the pulmonary endothelium. Notably, FXN-dependent endothelial senescence was also demonstrated in inducible pluripotent stem cells-derived endothelial cells from patients with FRDA, offering a plausible explanation for a predisposition to PH, independent of or additive to left ventricular dysfunction. Altogether, these data demonstrate that epigenetic or genetic FXN deficiency orchestrates Fe-S-dependent metabolic and replication stress which converge on irreversible senescence, signifying a novel endothelial-specific mechanism across PH subtypes, including PH due to left heart disease. In doing so, this work offers foundational evidence for the identification of a cohort of FRDA patients at risk for PH and endorse several Fe-S-related treatment options including senotherapies.


Social Networking:
Share |


Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Culley, Mirandamkc53@pitt.edumkc530000-0002-1546-4874
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorChan,
Committee ChairMars,
Committee MemberVan Houten,
Committee MemberOury,
Committee MemberMorris,
Committee MemberGladwin,
Date: 1 October 2020
Date Type: Publication
Defense Date: 3 August 2020
Approval Date: 1 October 2020
Submission Date: 18 August 2020
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 183
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Cellular and Molecular Pathology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Pulmonary hypertension, endothelium, senescence, metabolism, replication stress, Friedreich's ataxia
Date Deposited: 01 Oct 2020 15:44
Last Modified: 01 Oct 2020 15:44


Monthly Views for the past 3 years

Plum Analytics

Actions (login required)

View Item View Item