A simplified illustration of cellular changes during ischaemia. This schematic shows that the absence of oxygen (O₂) inactivates Complex IV and the electron transport chain, thus preventing ATP generation through the F₁-ATPase. This leads to increased glycolysis and the production of lactate, which acidifies the cytosol. NHE is thus stimulated to exchange H⁺ ions for Na⁺, and increased cytosolic Na⁺ in turn activates NCX, leading to increased cytosolic Ca²⁺. During ischaemia, mitochondrial Ca²⁺ is thought to increase. The rise of mitochondrial Ca²⁺ is canonically attributed to transport of cytosolic Ca²⁺ into the mitochondrial matrix via MCU, though this has not been directly proven. Overaccumulation of mitochondrial Ca²⁺ is thought to trigger opening of PTP, which may be inhibited by low pH during ischaemia but could become activated upon reperfusion. PTP opening is thought to lead to cell death.