mitochondria role in reperfusion injury
Neurodegeneration following stroke has roughly the same pathogenic mechanisms as in ischaemic heart disease (i.e. Ca overload, loss of mitochondrial membrane potential, leading to mPTP opening, ROS production leading to oxidative damage, ATP depletion). Nonetheless, one of the key differences arises in the source of calcium overload. In neurons, excess Ca entry is mediated by ionotropic receptors (Choi, 1987), NMDA receptors (NMDARs) and AMPA receptors (AMPARs).
NMDARs are highly permeable to Ca and Na, and overactivation of NMDARs is sufficient to induce death (Hardingham et al 2002). Selective NMDAR blocks reduce excitotoxic damage (Choi et al 1988).
AMPARs mediate fast neurotransmission and are normally impermeable to Ca, but Ca-permeable AMPARs are thought to contribute to neuronal injury during ischaemia and levels of these receptors are regulated in response to physiological states including ischemia.
The mitochondrial calcium uniporter (MCU) allows mitochondria to take up Ca and is an important mediator for Ca uptake in neurons following ischaemia. Excess Ca uptake uncouples electron transfer from ATP synthesis and ATP depletion increases free radical production.