Mitochondrial Complex IV Subunit 4 Isoform 2 Is Essential for Acute Pulmonary Oxygen Sensing

Area of Science:

• Pulmonary physiology
• Mitochondrial biology
• Cell signaling

Background:

• Acute pulmonary oxygen sensing is vital for preventing hypoxemia via hypoxic pulmonary vasoconstriction (HPV).
• Mitochondrial superoxide release is implicated in HPV signaling, but the primary sensor and mechanism remain unclear.
• The role of Cox4i2 in acute and chronic pulmonary oxygen sensing is not well understood.

Purpose of the Study:

• To investigate the function of Cox4i2 in pulmonary oxygen sensing.
• To determine the roles of superoxide and hydrogen peroxide in Cox4i2-mediated signaling.
• To elucidate the mechanism of acute and chronic hypoxia responses in the lungs.

Main Methods:

• Utilized Cox4i2 knockout (Cox4i2-/-) mice and isolated lung preparations.
• Measured hypoxic pulmonary vasoconstriction (HPV) in ventilated and perfused lungs.
• Assessed intracellular calcium in pulmonary arterial smooth muscle cells (PASMCs) via electron spin resonance spectroscopy and patch-clamp electrophysiology.
• Analyzed mitochondrial membrane potential and reactive oxygen species production.

Main Results:

• Cox4i2 deficiency abolished acute HPV and hypoxia-induced calcium increases in PASMCs.
• Hypoxia-induced mitochondrial superoxide release was absent in Cox4i2-/- PASMCs.
• Mitochondrial hyperpolarization during hypoxia was dependent on Cox4i2.
• Hydrogen peroxide normalized hypoxia-induced cellular membrane depolarization in Cox4i2-/- PASMCs.
• Cox4i2 deficiency had minimal impact on chronic hypoxia-induced pulmonary hypertension and vascular remodeling.

Conclusions:

• Cox4i2 is essential for acute pulmonary oxygen sensing and HPV.
• Cox4i2 triggers mitochondrial hyperpolarization and superoxide release, which is converted to hydrogen peroxide, leading to cellular depolarization and HPV.
• These findings establish a novel model for pulmonary oxygen sensing involving Cox4i2 and mitochondrial signaling.