Mitochondrial Fission Contributes to Diaphragmatic Weakness Induced by Mechanical Ventilation

Stephan Matecki, H Dridi, M Yehya, Robert J. Barsotti, Y Liu, S Reiken, L Azria, R Soni, A Marks, A Lacampagne

Research output: Contribution to conferencePresentation


In critical care patients, acute diaphragm unloading due to mechanical ventilation (MV) initiates a process of diaphragmatic dysfunction and atrophy referred to as ventilator-induced diaphragm dysfunction (VIDD). Although, mitochondrial dysfunction linked to oxidative stress, plays a critical role in VIDD, the precise molecular mechanism remains poorly understood. Herein we aimed to dissect the role of mitochondrial fragmentation as an early mechanism in VIDD and as a potential therapeutic intervention.Design: Experimental randomized studySetting: Research laboratorySubjects: C57/BL6 miceInterventions: Three groups of C57/BL6 mice were used. One group ventilated for six hours, one ventilated for six hours and treated with an inhibitor of mitochondrial fragmentation (P110) and one non-ventilated group which served as a control.Measurements and Main Results: We evaluated the whole cell proteomic changes, the activated cellular pathways in VIDD, the structure and function of the mitochondria and ryanodine receptor type 1 (RyR1) and the diaphragm force production in the three groups. We found that six hours of MV resulted in a mitochondrial fission, associated with increased levels of dynamin related protein 1 (DRP1) binding to the mitochondria, increased mitochondrial ROS production, RyR1 oxidation and Ca2+ leak, and loss of diaphragm strength. We, also, found that all these changes were prevented by P110, a molecule that blocks the recruitment of DRP1 to its receptor FIS1 on the outer of the mitochondrial membrane. Conclusions: We report that MV induces mitochondrial fragmentation and dysfunction in the diaphragms which is associated with an up/down regulation of 320 proteins, mainly related to mitochondrial function and which can be prevented by P110. Moreover, the pharmacological intervention rescued the VIDD phenotype.
Original languageAmerican English
StatePublished - May 2023
EventAmerican Thoracic Society International Conference 2023 - Washington, DC
Duration: May 1 2023 → …


ConferenceAmerican Thoracic Society International Conference 2023
Period5/1/23 → …


  • Medicine and Health Sciences

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