Pauline Esteves1,2, Landry Blanc1,3, Alexis Celle1,2, Isabelle Dupin1,2, Elise Maurat1,2, Nivea Amoedo1,2, Guillaume Cardouat1,2, Olga Ousova1,2, Lara Gales4, Florian Bellvert4, Hugues Begueret5, Matthieu Thumerel1,2,5, Jean-William Dupuy1,3, Nicolas Desbenoit1,3, Roger Marthan1,2,5, Pierre-Olivier Girodet1,2,5, Rodrigue Rossignol1,2, Patrick Berger1,2,5,6, Thomas Trian7,2,6. 1. Centre de Recherche Cardio-thoracique de Bordeaux, U1045, MRGM, Functional Genomics Center (CGFB), CIC 1401, CELLOMET, Univ-Bordeaux, Bordeaux, France. 2. Centre de Recherche Cardio-thoracique de Bordeaux, U1045, U1211, CIC 1401, INSERM, Bordeaux, France. 3. CNRS, UMR5248, Institute of Chemistry & Biology of Membranes & Nano objects, Functional Genomics Center (CGFB), Proteomics Facility, Université de Bordeaux, Bordeaux, France. 4. CNRS 5504, INRA 792, INSA Toulouse, Toulouse Biotechnology Institute, Bio & Chemical Engineering, Université de Toulouse, MetaToul, Toulouse, France. 5. Service d'exploration fonctionnelle respiratoire, Service de chirurgie thoracique, Service d'anatomopathologie, CIC 1401, CHU de Bordeaux, Bordeaux, France. 6. Co-last author. 7. Centre de Recherche Cardio-thoracique de Bordeaux, U1045, MRGM, Functional Genomics Center (CGFB), CIC 1401, CELLOMET, Univ-Bordeaux, Bordeaux, France thomas.trian@u-bordeaux.fr.
Abstract
BACKGROUND: Bronchial smooth muscle (BSM) remodelling in asthma is related to an increased mitochondrial biogenesis and enhanced BSM cell proliferation in asthma. Since (i) mitochondria produce the highest levels of cellular energy and (ii) fatty acid beta-oxidation is the most powerful way to produce ATP, we hypothesized that, in asthmatic BSM cells, energetic metabolism is shifted towards the beta-oxidation of fatty acids. OBJECTIVES: We aimed to characterize BSM cell metabolism in asthma both in vitro and ex vivo to identify a novel target for reducing BSM cell proliferation. METHODS: Twenty-one asthmatic and 31 non-asthmatic patients were enrolled. We used metabolomic and proteomic approaches to study BSM cells. Oxidative stress, ATP synthesis, fatty acid endocytosis, metabolite production, metabolic capabilities, mitochondrial networks, cell proliferation and apoptosis were assessed on BSM cells. Fatty acid content was assessed in vivo using MALDI-spectrometry imaging. RESULTS: Asthmatic BSM cells were characterized by an increased rate of mitochondrial respiration with a stimulated ATP production and mitochondrial β-oxidation. Fatty acid consumption was increased in asthmatic BSM both in vitro and ex vivo. Proteome remodelling of asthmatic BSM occurred via 2 canonical mitochondrial pathways. The levels of CPT2 and LDL-receptor, which internalize fatty acids through mitochondrial and cell membranes, respectively, were both increased in asthmatic BSM cells. Blocking CPT2 or LDL-receptor drastically and specifically reduced asthmatic BSM cell proliferation. CONCLUSION: This study demonstrates a metabolic switch towards mitochondrial beta-oxidation in asthmatic BSM and identifies fatty acid metabolism as a new key target to reduce BSM remodelling in asthma.
BACKGROUND: Bronchial smooth muscle (BSM) remodelling in asthma is related to an increased mitochondrial biogenesis and enhanced BSM cell proliferation in asthma. Since (i) mitochondria produce the highest levels of cellular energy and (ii) fatty acid beta-oxidation is the most powerful way to produce ATP, we hypothesized that, in asthmatic BSM cells, energetic metabolism is shifted towards the beta-oxidation of fatty acids. OBJECTIVES: We aimed to characterize BSM cell metabolism in asthma both in vitro and ex vivo to identify a novel target for reducing BSM cell proliferation. METHODS: Twenty-one asthmatic and 31 non-asthmatic patients were enrolled. We used metabolomic and proteomic approaches to study BSM cells. Oxidative stress, ATP synthesis, fatty acid endocytosis, metabolite production, metabolic capabilities, mitochondrial networks, cell proliferation and apoptosis were assessed on BSM cells. Fatty acid content was assessed in vivo using MALDI-spectrometry imaging. RESULTS: Asthmatic BSM cells were characterized by an increased rate of mitochondrial respiration with a stimulated ATP production and mitochondrial β-oxidation. Fatty acid consumption was increased in asthmatic BSM both in vitro and ex vivo. Proteome remodelling of asthmatic BSM occurred via 2 canonical mitochondrial pathways. The levels of CPT2 and LDL-receptor, which internalize fatty acids through mitochondrial and cell membranes, respectively, were both increased in asthmatic BSM cells. Blocking CPT2 or LDL-receptor drastically and specifically reduced asthmatic BSM cell proliferation. CONCLUSION: This study demonstrates a metabolic switch towards mitochondrial beta-oxidation in asthmatic BSM and identifies fatty acid metabolism as a new key target to reduce BSM remodelling in asthma.
Authors: Priyadarshini Kachroo; Joanne E Sordillo; Sharon M Lutz; Scott T Weiss; Rachel S Kelly; Michael J McGeachie; Ann Chen Wu; Jessica A Lasky-Su Journal: J Pers Med Date: 2021-11-04