Role and regulation of mitochondrial permeability transition in cell death

Abstract

The role of the Mitochondrial Permeability Transition (MPT) in apoptosis and necrosis is controversial. Here we show that the MPT regulates the release of cytochrome c for apoptosis during endoplasmic reticulum (ER) stress by remodeling the cristae junction (CJ). CEM cells were treated with the ER-stressor thapsigargin (THG) which led to cyclophilin-D-dependent mitochondrial release of the profusion GTPase Optic Atrophy 1 (OPA1), which controls CJ integrity, and cytochrome c leading to apoptosis. Interference RNA knockdown of Bax blocked OPA1 and cytochrome c release after THG treatment, but did not prevent the MPT showing that Bax was essential for cytochrome c release by MPT. In isolated mitochondria, MPT led to OPA1 and cytochrome c release independently of VDAC and the outer membrane indicating that the MPT is an inner membrane phenomenon. Lastly, the MPT was regulated by the electron transport chain since THG-induced cell death was inhibited in cells lacking mtDNA.