During reperfusion injury following myocardial ischemia, mitochondria play a central role in the amplification of cell death. The mitochondrial permeability transition pore (MPTP) opens during reperfusion. Which molecular event specifically triggers MPTP opening during reperfusion but NOT during ischemia alone?

• A Sustained mitochondrial membrane hyperpolarization during ischemia accumulates protons that trigger MPTP on reperfusion
• B Rapid restoration of pH on reperfusion activates Ca2+-sensitive MPTP components; the ischemic acidosis had paradoxically inhibited MPTP, and pH normalization during reperfusion unmasks Ca2+ overload-driven pore opening ✓
• C Restoration of oxygen delivery directly activates caspase-3 in the inner mitochondrial membrane
• D Reperfusion-induced ATP depletion activates AMPK, which phosphorylates VDAC to form the MPTP

Explanation

Paradoxically, ischemic acidosis (pH 6.2–6.5) inhibits MPTP opening because MPTP components (cyclophilin D, ANT) are inhibited at low pH. During ischemia, mitochondrial Ca2+ overload and ROS accumulate but MPTP remains closed. When blood flow is restored (reperfusion), the rapid restoration of pH toward neutral, combined with a burst of ROS from re-activated electron transport and mitochondrial Ca2+ overload, provides the dual trigger (Ca2+ + pH normalization) for cyclophilin D-dependent MPTP opening. This causes inner membrane permeabilization, mitochondrial swelling, cytochrome c release, and both apoptotic and necrotic death, constituting 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.