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PGAM5 is a key driver of mitochondrial dysfunction in experimental lung fibrosis

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Abstract

Rationale

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.

Methods

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.

Results

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.

Conclusions

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.

Graphical abstract

Toxic agents lead to mitochondrial damage resulting in depolarization of the mitochondrial membrane potential (ΔΨ) which is a gateway event for the initiation of PGAM5-mediated mitophagy. PGAM5-mediated mitophagy in turn leads to a self-perpetuating escalation of ΔΨ depolarization. Loss of the mitophagy-based damage-enhancing loop under PGAM5-deficient conditions breaks this vicious cycle, leading to improved mitochondrial homeostasis.

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Acknowledgements

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.

Funding

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).

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Authors and Affiliations

  1. Department of Medicine 1, University Hospital, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany

    Ingo Ganzleben, Gui-Wei He, Claudia Günther, Markus F. Neurath & Christoph Becker

  2. Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany

    Elena-Sophie Prigge

  3. Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Elena-Sophie Prigge

  4. Central Unit Electron Microscopy, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Karsten Richter

  5. Department of Pathology, University Hospital, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany

    Ralf J. Rieker

  6. Department of Medicine 5, University Hospital, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany

    Dimitrios Mougiakakos

Authors
  1. Ingo Ganzleben
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  2. Gui-Wei He
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Contributions

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.

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Correspondence to Christoph Becker.

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Ganzleben, I., He, GW., Günther, C. et al. PGAM5 is a key driver of mitochondrial dysfunction in experimental lung fibrosis. Cell. Mol. Life Sci. 76, 4783–4794 (2019). https://doi.org/10.1007/s00018-019-03133-1

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  • DOI: https://doi.org/10.1007/s00018-019-03133-1

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