The mitochondrial cardiolipin remodeling enzyme lysocardiolipin acyltransferase is a novel target in pulmonary fibrosis

Long Shuang Huang, Biji Mathew, Haiquan Li, Yutong Zhao, Shwu Fan Ma, Imre Noth, Sekhar P. Reddy, Anantha Harijith, Peter V. Usatyuk, Evgeny V. Berdyshev, Naftali Kaminski, Tong Zhou, Wei Zhang, Yanmin Zhang, Jalees Rehman, Sainath R. Kotha, Travis O. Gurney, Narasimham L. Parinandi, Yves A. Lussier, Joe G.N. GarciaViswanathan Natarajan

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

Rationale: Lysocardiolipin acyltransferase (LYCAT), a cardiolipin-remodeling enzyme regulating the 18:2 linoleic acid pattern of mammalian mitochondrial cardiolipin, is necessary for maintaining normal mitochondrial function and vascular development. We hypothesized that modulation of LYCAT expression in lung epithelium regulates development of pulmonary fibrosis. Objectives: To define a role for LYCAT in human and murine models of pulmonary fibrosis. Methods: We analyzed the correlation of LYCAT expression in peripheral blood mononuclear cells (PBMCs) with the outcomes of pulmonary functions and overall survival, and used the murine models to establish the role of LYCAT in fibrogenesis. We studied the LYCAT action on cardiolipin remodeling, mitochondrial reactive oxygen species generation, and apoptosis of alveolar epithelial cells under bleomycin challenge. Measurements and Main Results: LYCAT expression was significantly altered in PBMCs and lung tissues from patients with idiopathic pulmonary fibrosis (IPF), which was confirmed in two preclinical murine models of IPF, bleomycin- and radiation-induced pulmonary fibrosis. LYCAT mRNA expression in PBMCs directly and significantly correlated with carbon monoxide diffusion capacity, pulmonary function outcomes, and overall survival. In both bleomycin- and radiation-induced pulmonary fibrosis murine models, hLYCAT overexpression reduced several indices of lung fibrosis, whereas down-regulation of native LYCAT expression by siRNA accentuated fibrogenesis. In vitro studies demonstrated that LYCAT modulated bleomycin-induced cardiolipin remodeling, mitochondrial membrane potential, reactive oxygen species generation, and apoptosis of alveolar epithelial cells, potential mechanisms of LYCAT-mediated lung protection. Conclusions: This study is the first to identify modulation of LYCAT expression in fibrotic lungs and offers a novel therapeutic approach for ameliorating lung inflammation and pulmonary fibrosis.

Original languageEnglish (US)
Pages (from-to)1402-1415
Number of pages14
JournalAmerican journal of respiratory and critical care medicine
Volume189
Issue number11
DOIs
StatePublished - Jun 1 2014

Keywords

  • Apoptosis
  • Bleomycin
  • IPF
  • LYCAT
  • Mitochondrial cardiolipin remodeling

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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    Huang, L. S., Mathew, B., Li, H., Zhao, Y., Ma, S. F., Noth, I., Reddy, S. P., Harijith, A., Usatyuk, P. V., Berdyshev, E. V., Kaminski, N., Zhou, T., Zhang, W., Zhang, Y., Rehman, J., Kotha, S. R., Gurney, T. O., Parinandi, N. L., Lussier, Y. A., ... Natarajan, V. (2014). The mitochondrial cardiolipin remodeling enzyme lysocardiolipin acyltransferase is a novel target in pulmonary fibrosis. American journal of respiratory and critical care medicine, 189(11), 1402-1415. https://doi.org/10.1164/rccm.201310-1917OC