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

Journal article

Publication Details

Author(s): Ganzleben I, He GW, Günther C, Prigge ES, Richter K, Rieker R, Mougiakakos D, Neurath M, Becker C
Journal: Cellular and Molecular Life Sciences
Publication year: 2019
ISSN: 1420-682X
eISSN: 1420-9071


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.[Figure not available: see fulltext.].

FAU Authors / FAU Editors

Becker, Christoph Prof. Dr. rer. nat.
Professur für Molekulare Gastroenterologie
Ganzleben, Ingo Dr. med.
Medizinische Klinik 1 - Gastroenterologie, Pneumologie und Endokrinologie
Medizinische Klinik 1 - Gastroenterologie, Pneumologie und Endokrinologie
Mougiakakos, Dimitrios
Professur für Hämatologie/Onkologie mit dem Schwerpunkt Tumorimmunologie
Neurath, Markus Prof. Dr.
Lehrstuhl für Innere Medizin I
Rieker, Ralf Prof. Dr.
Pathologisches Institut

External institutions with authors

Deutsches Krebsforschungszentrum (DKFZ)
Universitätsklinikum Heidelberg

How to cite

Ganzleben, I., He, G.W., Günther, C., Prigge, E.S., Richter, K., Rieker, R.,... Becker, C. (2019). PGAM5 is a key driver of mitochondrial dysfunction in experimental lung fibrosis. Cellular and Molecular Life Sciences.

Ganzleben, Ingo, et al. "PGAM5 is a key driver of mitochondrial dysfunction in experimental lung fibrosis." Cellular and Molecular Life Sciences (2019).


Last updated on 2019-26-06 at 10:47