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Frataxin Deficiency Coordinates Iron-Sulfur-Dependent Metabolic and Genomic Stress to Promote Endothelial Senescence in Pulmonary Hypertension

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Frataxin Deficiency Coordinates Iron-Sulfur-Dependent Metabolic and Genomic Stress to Promote Endothelial Senescence in Pulmonary Hypertension Title Page Frataxin deficiency coordinates iron-sulfur-dependent metabolic and genomic stress to promote endothelial senescence in pulmonary hypertension by Miranda Kay Culley Bachelor of Arts, Case Western Reserve University, 2014 Submitted to the Graduate Faculty of the School of Medicine in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2020 Committee Page UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE This dissertation was presented by Miranda Kay Culley It was defended on August 3, 2020 and approved by Mark Gladwin, M.D., Jack D. Myers Professor and Chair of the Department of Medicine Wendy Mars, Ph.D., Associate Professor, Department of Pathology Alison Morris, M.D., M.S., Professor, Department of Medicine Timothy Oury, M.D., Ph.D., Professor, Department of Pathology Bennett Van Houten, Ph.D., Richard M. Cyert Professor of Molecular Oncology, Department of Pharmacology and Chemical Biology Dissertation Director: Stephen Y. Chan, M.D., Ph.D., Professor, Department of Medicine ii Copyright © by Miranda Kay Culley 2020 iii Abstract Frataxin deficiency coordinates iron-sulfur-dependent metabolic and genomic stress to promote endothelial senescence in pulmonary hypertension Miranda Kay Culley, Ph.D. University of Pittsburgh, 2020 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 iv 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. v Table of Contents Preface ......................................................................................................................................... xiii 1.0 Introduction ............................................................................................................................. 1 1.1 Pulmonary hypertension ................................................................................................ 1 1.1.1 Cellular pathology ................................................................................................1 1.1.1.1 Controversial endothelial phenotypes.................................................... 2 1.1.2 Molecular pathology ............................................................................................3 1.1.2.1 Mitochondrial dysfunction ...................................................................... 3 1.1.2.2 DNA damage ............................................................................................ 5 1.1.3 Epidemiology and classification ..........................................................................6 1.1.4 Prognosis and therapies .......................................................................................9 1.2 Iron-sulfur clusters ....................................................................................................... 12 1.2.1 Iron-sulfur biogenesis ........................................................................................13 1.2.2 Pulmonary hypertension in diseases due to Fe-S biogenesis gene deficiency .......................................................................................................................................14 1.3 Friedreich’s ataxia ........................................................................................................ 16 1.3.1 Trinucleotide repeat mutations in frataxin .....................................................16 1.3.2 Epidemiology and clinical presentation ...........................................................17 1.3.2.1 Hypertrophic cardiomyopathy ............................................................. 17 1.3.3 Cellular and molecular pathology ....................................................................18 1.3.4 Emerging therapies ............................................................................................19 1.4 Rationale ........................................................................................................................ 21 vi 2.0 Frataxin deficiency disrupts pulmonary endothelial metabolism .................................... 23 2.1 Introduction .................................................................................................................. 23 2.2 Materials & Methods ................................................................................................... 26 2.3 Primary Data ................................................................................................................ 31 2.3.1 FXN knockdown attenuated mitochondrial respiration and elevated reactive oxygen species ..............................................................................................................31 2.3.2 FXN-dependent metabolic reprogramming contributes to endothelial dysfunction consistent with PH ..................................................................................34 2.4 Supplemental Data ....................................................................................................... 37 2.5 Discussion ...................................................................................................................... 39 3.0 FXN deficiency promotes pulmonary endothelial evolution from acute replication stress to cellular senescence........................................................................................................ 42 3.1 Introduction .................................................................................................................. 43 3.2 Materials & Methods ................................................................................................... 44 3.3 Primary Data ................................................................................................................ 51 3.3.1 Acute replication stress and cell cycle arrest in FXN-deficient endothelial cells .......................................................................................................................................51 3.3.2 Sustained FXN deficiency leads to persistent DNA damage response and endothelial senescence .................................................................................................55 3.3.3 FXN deficiency promotes endothelial senescence and PH in vivo .................57 3.4 Supplemental Data ....................................................................................................... 62 3.5 Discussion ...................................................................................................................... 64 vii 4.0 HIF-dependent epigenetic modulation drives acquired FXN deficiency and endothelial senescence in multiple PH subtypes ...................................................................... 69 4.1 Introduction .................................................................................................................. 69 4.2 Materials & Methods ................................................................................................... 71 4.3 Primary Data ...............................................................................................................
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