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Updated: Jul 11, 2025
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Repeated Measurement of Respiratory Muscle Activity and Ventilation in Mouse Models of Neuromuscular Disease
Published on: April 17, 2017
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Aberrant mitochondrial dynamics contributes to diaphragmatic weakness induced by mechanical ventilation
Haikel Dridi1,2, Marc Yehya3, Robert Barsotti4
1Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, NewYork, NY 10032, USA.
PNAS Nexus
|November 13, 2023
Summary
Mechanical ventilation causes diaphragm dysfunction by altering mitochondrial dynamics and function. A P110 inhibitor prevented these changes, suggesting potential treatments for ventilator-induced diaphragm dysfunction (VIDD).
Area of Science:
- Biomedical Science
- Cell Biology
- Critical Care Medicine
Background:
- Mechanical ventilation (MV) can lead to ventilator-induced diaphragm dysfunction (VIDD).
- Mitochondrial dysfunction and oxidative stress are implicated in VIDD, but mechanisms are unclear.
- Diaphragm inactivity during MV causes atrophy and dysfunction.
Purpose of the Study:
- To investigate the molecular mechanisms of VIDD, focusing on mitochondrial dynamics and function.
- To identify potential therapeutic targets for preventing VIDD.
Main Methods:
- Studied diaphragm tissue from patients on MV.
- Analyzed mitochondrial dynamics, reactive oxygen species (ROS) production, and protein expression.
- Utilized proteomics to assess global protein changes.
- Administered P110, a dynamin-related protein 1 (DRP1) inhibitor.
Main Results:
- MV induced mitochondrial fragmentation and dysfunction, increasing DRP1 expression.
- Mitochondria showed increased ROS production and altered calcium handling (RyR1 oxidation, calstabin 1 decrease).
- P110 treatment prevented MV-induced mitochondrial and contractile dysfunction.
- Proteomics revealed significant changes in mitochondrial function-related proteins.
Conclusions:
- MV causes diaphragm mitochondrial fragmentation and dysfunction via DRP1.
- Mitochondrial dysfunction contributes to impaired calcium handling and reduced contractile function in VIDD.
- Targeting mitochondrial fission/fusion balance with inhibitors like P110 may mitigate VIDD.
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