Biology subjects

Sciurba, F. C.

Publications and source records attributed to Sciurba, F. C..

4 recordsLinked to original sources

bioRxiv2026

Epithelial QKI Protects Against Emphysema by Maintaining Mitochondrial Integrity

Single-cell transcriptomic profiling of chronic obstructive pulmonary disease (COPD) lungs identified QKI, an RNA-binding protein, as a candidate emphysema-associated gene, but its epithelial role in COPD pathobiology remains unclear. We show that QKI expression is reduced in human COPD lungs and that alveolar type 2 epithelial (AT2) cell QKI protein levels correlate strongly with spirometric indices and diffusing capacity (DLCO). Lung epithelium-specific QKI knockout mice (QKI{Delta}/{Delta}) developed spontaneous airspace enlargement with emphysema-like mechanics, and QKI-deficient AT2 cells showed impaired spheroid colony formation and increased apoptosis. Integrated transcriptomic and proteomic analyses of primary AT2 cells revealed a selective reduction in functional mitochondrial (respiratory-chain and metabolic) protein abundance despite relatively preserved transcript levels, consistent with mitochondrial transcriptome-proteome discordance. QKI loss increased mtDNA abundance and TOMM20 staining but decreased ATP5A, indicating accumulation of structurally increased but functionally dysfunctional mitochondria. In human epithelial cells, CRISPR-mediated QKI deficiency reduced oxidative respiration, increased glycolytic reliance, elevated mitochondrial ROS and membrane potential, and increased apoptosis; these phenotypes were partially rescued by QKI re-expression. These findings identify epithelial QKI as a regulator of mitochondrial integrity and stress tolerance in COPD.

cell biology↗

bioRxiv2021

Extracellular release of mitochondrial DNA is triggered by cigarette smoke and is detected in COPD

Chronic obstructive pulmonary disease (COPD) is characterized by continuous and irreversible inflammation frequently caused by persistent exposure to toxic inhalants such as cigarette smoke (CS). CS may trigger mitochondrial DNA (mtDNA) extrusion into the cytosol, extracellular space, or foster its transfer by extracellular vesicles (EVs). The present study aimed to elucidate whether mtDNA is released upon CS exposure and in COPD. We measured cell-free mtDNA (cf-mtDNA) in the plasma of former smokers affected by COPD, in the serum of mice that developed CS-induced emphysema, and in the extracellular milieu of human bronchial epithelial cells exposed to cigarette smoke extract (CSE). Further, we characterized cells exposed to sublethal and lethal doses of CSE by measuring mitochondrial membrane potential and dynamics, superoxide production and oxidative stress, cell cycle progression, and cytokine expression. Patients with COPD and mice that developed emphysema showed increased levels of cf-mtDNA. In cell culture, exposure to a sublethal dose of CSE decreased mitochondrial membrane potential, increased superoxide production and oxidative damage, dysregulated mitochondrial dynamics, and triggered mtDNA release in extracellular vesicles. The release of mtDNA into the extracellular milieu occurred concomitantly with increased expression of DNase III, DNA-sensing receptors (cGAS, NLRP3), proinflammatory cytokines (IL-1{beta}, IL-6, IL-8, IL-18, CXCL2), and markers of senescence (p16, p21). Exposure to a lethal dose of CSE preferentially induced mtDNA and nuclear DNA release in cell debris. Our findings demonstrate that CS-induced stress triggers mtDNA release and is associated with COPD, supporting cf-mtDNA as a novel signaling response to CS exposure.

cell biology↗

bioRxiv2020

Adenine Nucleotide Translocase regulates the airway epithelium, mitochondrial metabolism and ciliary function

Airway hydration and ciliary function are critical to airway homeostasis and dysregulated in chronic obstructive lung disease (COPD). COPD is the 4th leading cause of death in the US and is impacted by cigarette smoking with no therapeutic options. We utilized a genetic selection approach in the amoeba Dictyostelium discoideum as a comparative discovery tool in lung biology to identify genetic protectors from cigarette smoke (CS). Adenine nucleotide translocase (ANT), a mitochondrial ADP/ATP transporter, was protective against CS in Dictyostelium and human bronchial epithelial cells. ANT2 gene expression is reduced in lung tissue from COPD patients and in a mouse smoking model. ANT1 and ANT2 overexpression resulted in enhanced oxidative respiration and ATP flux. In addition to ANTs presence in the mitochondria, ANT1 and ANT2 reside at the plasma membrane in airway epithelial cells and this localization plays a role in how ANTs regulate airway homeostasis. ANT2 overexpression stimulates airway surface liquid hydration by ATP and maintains ciliary beating after CS exposure, which are key functions of the airway. Our study highlights the potential of ANT modulation in protecting from dysfunctional mitochondrial metabolism, airway hydration, and ciliary motility in COPD.

cell biology↗

bioRxiv2019

Unpaired Data Empowers Association Tests

To achieve a holistic view of the underlying mechanisms of human diseases, the biomedical research community is moving toward harvesting retrospective data available in Electronic Healthcare Records (EHRs). The first step for causal understanding is to perform association tests between types of potentially high-dimensional biomedical data, such as genetic, blood biomarkers, and imaging data. To obtain a reasonable power, current methods require a substantial sample size of individuals with both data modalities. This prevents researchers from using much larger EHR samples that include individuals with at least one data type, limits the power of the association test, and may result in higher false discovery rate. We present a new method called the Semi-paired Association Test (SAT) that makes use of both paired and unpaired data. In contrast to classical approaches, incorporating unpaired data allows SAT to produce better control of false discovery and, under some conditions, improve the association test power. We study the properties of SAT theoretically and empirically, through simulations and application to real studies in the context of Chronic Obstructive Pulmonary Disease. Our method identifies an association between the high-dimensional characterization of Computed Tomography (CT) chest images and blood biomarkers as well as the expression of dozens of genes involved in the immune system.

bioinformatics↗