Mechanical ventilation triggers abnormal mitochondrial dynamics and morphology in the diaphragm

Area of Science:

• Physiology
• Cell Biology
• Muscle Biology

Background:

• The diaphragm is essential for breathing and normally active throughout life.
• Mechanical ventilation (MV) is a medical intervention that inactivates the diaphragm, leading to muscle atrophy, damage, and weakness.
• Mitochondrial dysfunction is implicated in diaphragm weakness during MV, with mitochondrial dynamics (fusion and fission) playing a key role.

Purpose of the Study:

• To investigate the impact of short-term MV on diaphragm mitochondrial morphology and dynamics.
• To determine if MV alters mitochondrial fission and fusion proteins in the diaphragm.

Main Methods:

• Utilized quantitative electron microscopy to analyze mitochondrial morphology in mouse diaphragm.
• Assessed the abundance and activation status of key mitochondrial dynamics proteins (Mfn2, OPA1, Drp1).
• Compared mitochondrial features in diaphragm muscle subjected to 6 hours of MV versus controls.

Main Results:

• Mechanical ventilation induced significant fragmentation (excessive fission) of intermyofibrillar (IMF) mitochondria, but not subsarcolemmal (SS) mitochondria.
• Physical interactions between mitochondrial membranes were reduced in IMF mitochondria during MV.
• While proteins promoting fusion (Mfn2, OPA1) remained unchanged, the abundance and activation of the fission protein Drp1 increased in the diaphragm following MV.

Conclusions:

• Early diaphragm contractile inactivity due to MV causes abnormal mitochondrial fragmentation.
• Increased mitochondrial fission, mediated by Drp1, is an early event in MV-induced diaphragm dysfunction.
• These morphological changes likely contribute to mitochondrial dysfunction, maladaptive signaling, and muscle weakness.