PGAM5 is a key driver of mitochondrial dysfunction in experimental lung fibrosis
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Mitochondrial homeostasis has recently emerged as a focal point in the pathophysiology of idiopathic pulmonary fibrosis (IPF), but conflicting data have been reported regarding its regulation. We speculated that phosphoglycerate mutase family member 5 (PGAM5), a mitochondrial protein at the intersection of multiple cell death and mitochondrial turnover pathways, might be involved in the pathogenesis of IPF.
PGAM5-deficient mice and human pulmonary epithelial cells were analyzed comparatively with PGAM5-proficient controls in a bleomycin-based model of pulmonary fibrogenesis. Mitochondria were visualized by confocal and transmission electron microscopy. Mitochondrial homeostasis was assessed using JC1 (ΔΨ) and flow cytometry.
PGAM5 plays an important role in pulmonary fibrogenesis. Pgam5−/− mice displayed significantly attenuated lung fibrosis compared to controls. Complementary, in vitro studies demonstrated that PGAM5 impaired mitochondrial integrity on a functional and structural level independently of mtROS-production. On a molecular level, reduced mitophagy caused by PGAM5 deficiency improved mitochondrial homeostasis.
Our study identifies PGAM5 as an important regulator of mitochondrial homeostasis in pulmonary fibrosis. Our data further indicate PGAM5-mediated mitophagy itself as a pivotal gateway event in the mediation of self-sustaining mitochondrial damage and membrane depolarization. Our work hereby highlights the importance of mitochondrial dynamics and identifies a potential therapeutic target that warrants further studies.
KeywordsMitophagy Bleomycin IPF
We thank Prof. J. Behrens (Lehrstuhl für Experimentelle Medizin II, Friedrich-Alexander-Universität Erlangen-Nürnberg) for providing the PGAM5 plasmid, Dr. T. Chiriac, Dr. S. Wirtz and Prof. M. von Knebel Doeberitz for supplying material. We thank H. Dorner, G. Förtsch, R. Mehr, S. Rößler, V. Thonn, S. Wallmüller, and A. Wandersee for excellent technical assistance. We thank Dr. M. Neßling for her contribution to the TEM studies.
I.G., M.F.N. and C.B. designed the research. I.G., G.-W.H., C.G., E.-S.P., K.R., R.J.R. and D.M. performed the experiments. I.G., M.F.N. and C.B. analyzed the data and wrote the paper. The authors have declared that no conflict of interest exists.
This study was supported by funding from the DFG project BE3686/2, research unit FOR2438, SFB1181, SFB796, SPP1656, and clinical research unit KFO257. The Interdisciplinary Center for Clinical Research (IZKF) Erlangen supported I.G. with a laboratory rotation grant and through participation in the Clinician Scientist Program and C.G. with a funding grant (Project A75).
Compliance with ethical standards
Conflict of interest
We, the authors, have no conflicting financial interests.
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