In reperfusion injury following myocardial ischemia, the 'oxygen paradox' involves rapid reintroduction of oxygen to ischemic mitochondria. Which event during the first minutes of reperfusion is most responsible for cardiomyocyte death that was not yet irreversible during ischemia?

• A Rapid normalization of cytosolic pH causing mitochondrial permeability transition pore (mPTP) opening ✓
• B Activation of caspase-3 by cytochrome c that leaked during ischemia
• C Excessive autophagy with mitophagy depleting healthy mitochondria
• D Complement activation on restored endothelium causing neutrophil margination

Explanation

During ischemia, cytosolic pH falls (lactic acidosis), and paradoxically this acidosis keeps the mitochondrial permeability transition pore (mPTP) closed. When blood flow is restored, rapid cytosolic pH normalization (via sodium-hydrogen exchanger and sodium-calcium exchanger activation) removes this protection — simultaneous ROS burst from re-energizing mitochondria and calcium overload then trigger irreversible mPTP opening, which dissipates the mitochondrial membrane potential and causes cell swelling, ATP depletion, and necrosis. This pH-dependent mPTP opening is the central mechanism of lethal reperfusion injury.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.