In ischemia-reperfusion injury, the paradoxical worsening of cell death upon restoration of blood flow is primarily attributed to which mechanism?

• A Immediate re-activation of ATP synthesis overwhelming the depleted ADP pool
• B Sudden restoration of normal pH reversing all cellular adaptations simultaneously
• C Autophagy over-activation consuming essential structural proteins during reperfusion
• D Calcium overload activating calpains, mitochondrial permeability transition pore (mPTP) opening, and burst of reactive oxygen species from xanthine oxidase and mitochondria ✓

Explanation

During ischemia, intracellular calcium accumulates (due to failure of Na+/K+ ATPase and reverse Na+/Ca++ exchange) and xanthine dehydrogenase is converted to xanthine oxidase. Reperfusion brings in oxygen which allows xanthine oxidase to generate a burst of superoxide; mitochondria also generate ROS upon resuming electron transport. Calcium overload opens the mitochondrial permeability transition pore (mPTP) causing mitochondrial swelling, cytochrome c release, and necrosis/apoptosis. Rapid pH normalization itself can be harmful by activating proteases.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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