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


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.[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

APA:
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. https://dx.doi.org/10.1007/s00018-019-03133-1

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

BibTeX: 

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