Figure 3.

Hypothetical role of CerS6/ceramide in mitochondria after cerebral IR. IR triggers glutamate-induced cytosolic Ca²⁺ influx into the mitochondria and an activation of mitochondrial CerS6 that elevates ceramide. Ceramide blocks the MPTP opening at a low conductance state, leading to increased Ca²⁺ in the mitochondrial matrix. This MPTP inactivation would allow mitochondria to support adequate ATP production for formation of the apoptosome, and might be responsible for the initial raise in ATP production (and hence Δψ) during apoptosis [135], an observation that corresponds well with the reported transient mitochondrial hyper-polarization in the apoptosis induced by IL-3 withdrawal [136]. Rising mitochondrial Ca²⁺ activates calpain 10, which could cleave protein components of the MPTP [137] resulting in the MPTP opening at a high conductance state, swelling, and rupture of the outer mitochondrial membrane leading to necrotic cell death.